CN106573939A

CN106573939A - Thieno [3,2-d] pyrimidine, furo [3,2,d] pyrimidine, and pyrrolo [3,2-d] pyrimidines useful for treating respiratory syncitial virus infections

Info

Publication number: CN106573939A
Application number: CN201580041342.0A
Authority: CN
Inventors: M.O.H.克拉克; R.L.马克曼; D.西格尔
Original assignee: Gilead Sciences Inc
Current assignee: Gilead Sciences Inc
Priority date: 2014-07-28
Filing date: 2015-07-22
Publication date: 2017-04-19
Anticipated expiration: 2035-07-22
Also published as: JP2020023590A; WO2016018697A1; SI3174870T1; EA032490B1; SG11201700213SA; US20180072755A1; PL3174870T3; KR102460181B1; AR101280A1; ES2910382T3; PT3693367T; TW201617350A; JP2022010149A; US10501476B2; EP3174870B1; PL3693367T3; CA2956571A1; US9828388B2; MX2017001284A; AU2015298207C1

Abstract

Provided herein are formulations, methods and substituted thieno[3,2-d]pyrimidine, furo[3,2-d]pyrimidine, and pyrrolo[3,2-d]pyrimidine compounds of Formula (I) for treating Pneumovirinae virus infections, including respiratory syncytial virus infections, as well as methods and intermediates for synthesis of substituted thieno[3,2-d]pyrimidine, furo[3,2-d]pyrimidine, and pyrrolo[3,2-d]pyrimidine compounds.

Description

For treating thieno [3,2-d] pyrimidine, the furo of respiratory syncytial virus infection [3,2-d] pyrimidine and pyrrolo- [3,2-d] pyrimidine

Technical field

This application provides for treating pneumonitis viruss subfamily (Pneumovirinae) virus infection (specifically including exhaling Inhale road syncytial virus infection) substituted thieno [3,2-d] pyrimidine, furo [3,2-d] pyrimidine and pyrrolo- [3,2-d] it is phonetic Acridine compound, method and pharmaceutical preparation, and for preparing the method and intermediate of the compound.

Background technology

Pneumonitis viruss subfamily virus is antisense (negative-sense), single strand RNA viruses, and which causes many prevalences The reason for human and animal's disease.Virus pneumonitis viruss subfamily subfamily be Paramyxoviridae family a part and including Human respiratory syncytial virus (HRSV).Almost all of child can be subjected to HRSV infection to before its two years old.HRSV be baby and The infected person of the main cause of child's lower respiratory infection, wherein 0.5%-2% needs to be in hospital.With morbus cardiacuses, lung The old people and adult of disease or Jing immunosuppressant those people also have the excessive risk for developing into serious HRSV diseases (http://www.cdc.gov/rsv/index.html).Currently without the vaccine of available prevention HRSV infection.Monoclonal anti Body palivizumab can be used for immunoprophylaxises, but which is using high-risk infants are limited to, for example, premature infant or suffer from congenital heart disease Or the baby of pneumonopathy, and for generally using, cost is usually too high.Additionally, nucleoside analogue ribavirin is criticized Accurate unique antiviral agent but offer limited effectiveness as treatment HRSV infection.Accordingly, it would be desirable to anti-pneumonitis viruss subfamily therapy.

Example for treating pyrrolo- [2,3-d] pyrimidine compound of virus infection is described in U.S.2012/ 0009147A1 (Cho et al.), U.S.2012/0020921A1 (Cho et al.), WO 2008/089105A2 (Babu et al.), WO 2008/141079A1 (Babu et al.), WO 2009/132135A1 (Butler et al.), WO 2010/002877A2 (Francom), WO 2011/035231A1 (Cho et al.), WO 2011/035250A1 (Butler et al.), WO 2011/ 150288A1 (Cho et al.), WO 2012/012465 (Cho et al.), WO 2012/012776A1 (Mackman et al.), WO 2012/037038 (Clarke et al.), WO 2012/087596A1 (Delaney et al.) and WO 2012/142075A1 (Girijavallabhan et al.).

Remain a need for can be used to treat the infection of Paramyxo viruss coe virus, infect including pneumonitis viruss subfamily virus, for example The new antiviral agent of HRSV infection, which is effective and has acceptable toxic characteristic.

The content of the invention

This application provides (including that treatment is breathed by people for the infection that treatment is caused by pneumonitis viruss subfamily virus family The infection that road syncytial viruses cause) compound, method and pharmaceutical preparation.

This application provides formula (I) compound, or its pharmaceutically acceptable salt：

Wherein：

X is selected from：O, S, NH or N (C₁-C₆Alkyl)；

R¹It is selected from：H、CH₃、CH₃, F, Cl and NH₂；

R²It is selected from：F、Cl、OR^a、NHR^a, CN and N₃；

R³It is selected from：CN、OR^a、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl ,-CH₂-O-C₁-C₆Alkyl ,-CH₂-S-C₁-C₆ Alkyl, C₃-C₄Cycloalkyl, azido, halogen, C₁-C₃Haloalkyl, SR^a、-CH₂-C₃-C₄Cycloalkyl ,-O-C₃-C

R³It is selected from：CN、OR^a、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl ,-CH₂-O-C₁-C₆Alkyl ,-CH₂-S-C₁-C₆ Alkyl, C₃-C₄Cycloalkyl, azido, halogen, C₁-C₃Haloalkyl, SR^a、-CH₂-C₃-C₄Cycloalkyl ,-O-C₃-C₄Cycloalkyl With-O-C₁-C₃Haloalkyl；

Or

Work as R²For OR^aWhen, choosing is formed together with the furan nucleuss that can be connected with them of two ORa groups of 2 ' and 3 ' positions From following structure：

R⁴It is selected from：H ,-C (=O) R⁶,-C (=O) OR⁶With-C (=O) NR⁶R⁷；

Or

a)R⁴For following formula group：

Wherein：

Each Y be O, S, NR,⁺N(O)(R)、N(OR)、⁺N (O) is (OR) or N-NR₂；With

W¹And W²Formation-Y together³(C(R^y)₂)₃Y³-；

Or W¹Or W²One of together with 3 ' hydroxyls be-Y³- and W¹Or W²In another be Formulas I a；

Or W¹And W²It is each independently the group of Formulas I a：

Wherein：

Each Y¹Independently be O, S, NR,⁺N(O)(R)、N(OR)、⁺N (O) is (OR) or N-NR₂；

Each Y²It independently is key, O, CR₂、-O-CR₂-、NR、⁺N(O)(R)、N(OR)、⁺N(O)(OR)、N-NR₂、S、S-S、S Or S (O) (O)₂；

Each Y³It independently is O, S or NR；

M1 is 0,1,2 or 3；

Each R^xIt independently is R^yOr following formula：

Wherein：

Each M2a, M2b and M2c independently are 0 or 1；

M2d is 0,1,2,3,4,5,6,7,8,9,10,11 or 12；

Each R^yIt independently is H, F, Cl, Br, I, OH, R ,-C (=Y¹) R ,-C (=Y¹) OR ,-C (=Y¹)N(R)₂、-N (R)₂、-⁺N(R)₃、-SR、-S(O)R、-S(O)₂R、-S(O)(OR)、-S(O)₂(OR) ,-OC (=Y¹) R ,-OC (=Y¹)OR、-OC (=Y¹)(N(R)₂) ,-SC (=Y¹) R ,-SC (=Y¹) OR ,-SC (=Y¹)(N(R)₂) ,-N (R) C (=Y¹) R ,-N (R) C (=Y¹) OR ,-N (R) C (=Y¹)N(R)₂、-SO₂NR₂、-CN、-N₃、-NO₂,-OR or W³；

Or two R in identical carbon atoms^yThe carbocyclic ring with 3,4,5,6 or 7 carboatomic ring atoms is formed together；

Or two R in identical carbon atoms^yFormed together with the carbon atom with 3,4,5,6 or 7 annular atoms Heterocycle, one of annular atom is selected from O or N and every other annular atom is carbon；

Each R independently is H, (C₁-C₈) alkyl, (C₁-C₈) replace alkyl, (C₂-C₈) thiazolinyl, (C₂-C₈) alkene that replaces Base, (C₂-C₈) alkynyl, (C₂-C₈) replace alkynyl, C₆-C₁₀Aryl, C₆-C₁₀Substituted aryl, 3- to 10- circle heterocycles, replace 3- to 10- circle heterocycles, 5- to 12- unit's heteroaryls, replace 5- to 12- unit's heteroaryls, aryl alkyl, replace aryl alkane Base, heteroaryl alkyl or substituted heteroaryl alkyl；With

W³For W⁴Or W⁵；

W⁴For R ,-C (Y¹)R^y、-C(Y¹)W⁵、-SO₂R^yOr-SO₂W⁵；

W⁵Selected from phenyl, naphthyl, C₃-C₈Carbocyclic ring or 3- to 10- circle heterocycles, wherein W⁵Independently by 0,1,2,3,4,5 or 6 Individual R^ySubstituent group；

Each R⁶And R⁷It independently is H, (C₁-C₈) alkyl, (C₂-C₈) thiazolinyl, (C₂-C₈) alkynyl, (C₄-C₈) carbocylic radical alkyl, C₆-C₁₀Aryl, C₆-C₁₀Substituted aryl, 5- to 10- unit's heteroaryls, 5- to the 10- unit's heteroaryls for replacing ,-C (=O) (C₁-C₈) Alkyl ,-S (O)_n(C₁-C₈) alkyl or aryl (C₁-C₈) alkyl；

Or R⁶And R⁷3- to 7- circle heterocycles are formed together with the nitrogen being connected with them, wherein any ring carbon of the heterocycle is former Son is optionally by-O- ,-S- or-NR^a- substitute；

And wherein each R⁶Or R⁷Each (C₁-C₈) alkyl, (C₂-C₈) thiazolinyl, (C₂-C₈) alkynyl or aryl (C₁-C₈) alkyl times Choosing is independently replaced selected from following substituent group by 1,2,3 or 4：Halogen, hydroxyl, CN, N₃、N(R^a)₂Or OR^a；And it is wherein each (the C₁-C₈) alkyl 1,2 or 3 non-end carbon atoms optionally by-O- ,-S- or-NR^a- substitute；Or

b)R⁴Selected from following group：

Wherein：

R⁸Selected from phenyl, 1- naphthyls, 2- naphthyls,

R⁹Selected from H and CH₃；

R¹⁰Selected from H or C₁-C₆Alkyl；With

R¹¹Selected from H, C₁-C₈Alkyl, benzyl, C₃-C₆Cycloalkyl and-CH₂-C₃-C₆Cycloalkyl；Or

c)R⁴Formed selected from following structure with the 3 ' hydroxy combining：

Detailed description of the invention

This application provides formula (I) compound, or its pharmaceutically acceptable salt, wherein X is S and R^a、R¹、R²、R³、R⁴、 R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、Y、Y¹、Y²、Y³、W¹、W²、W³、W⁴、W⁵、M1、M2a、M2b、M2c、M2d、R^xAnd R^ySuch as formula above (I) defined.

This application provides formula (I) compound, or its pharmaceutically acceptable salt, wherein X is O and R^a、R¹、R²、R³、R⁴、 R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、Y、Y¹、Y²、Y³、W¹、W²、W³、W⁴、W⁵、M1、M2a、M2b、M2c、M2d、R^xAnd R^ySuch as formula above (I) defined.

This application provides formula (I) compound, or its pharmaceutically acceptable salt, wherein X is NH or N (C₁-C₆Alkyl) and R^a、R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、Y、Y¹、Y²、Y³、W¹、W²、W³、W⁴、W⁵、M1、M2a、M2b、M2c、M2d、R^x And R^yAs formula (I) is defined above.

Each embodiment, provides other embodiments, which includes the compound in the embodiment, or its pharmacy Upper acceptable salt, wherein R³It is selected from：CN、OR^a、C₁-C₄Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl ,-CH₂-O-C₁-C₄Alkyl ,- CH₂-S-C₁-C₄Alkyl, C₃-C₄Cycloalkyl, azido, halogen, C₁-C₃Chlorine alkyl, C₁-C₃Bromine alkyl and C₁-C₃Fluoroalkyl；And institute There are other variables, including X, R^a、R¹、R²、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、Y、Y¹、Y²、Y³、W¹、W²、W³、W⁴、W⁵、M1、 M2a、M2b、M2c、M2d、R^xAnd R^yAs defined in embodiments hereinbefore.

Each embodiment, provides other embodiments, which includes the compound in the embodiment, or its pharmacy Upper acceptable salt, wherein R³It is selected from：CN、OR^a、C₁-C₃Alkyl, C₂-C₃Thiazolinyl, C₂-C₃Alkynyl ,-CH₂-O-C₁-C₃Alkyl ,- CH₂-S-C₁-C₃Alkyl, C₃-C₄Cycloalkyl, azido, halogen, C₁-C₃Chlorine alkyl, C₁-C₃Bromine alkyl and C₁-C₃Fluoroalkyl；And institute There are other variables, including X, R^a、R¹、R²、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、Y、Y¹、Y²、Y³、W¹、W²、W³、W⁴、W⁵、M1、 M2a、M2b、M2c、M2d、R^xAnd R^yAs defined in embodiments hereinbefore.

Present invention also provides formula (I) compound, or its pharmaceutically acceptable salt, wherein：

R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：OH、F、Cl、N₃、NH₂And CN；

R³It is selected from：CN、N₃, methyl, ethyl, propyl group, vinyl, acrylic, acetenyl, CH₂F、CHF₂、CH₂Cl、CH₂SMe And CH₂OMe；With

X、R^a、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、Y、Y¹、Y²、Y³、W¹、W²、W³、W⁴、W⁵、M1、M2a、M2b、M2c、 M2d、R^xAnd R^yAs formula (I) is defined above.

X is S；

R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：OH、F、Cl、N₃、NH₂And CN；

R^a、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、Y、Y¹、Y²、Y³、W¹、W²、W³、W⁴、W⁵、M1、M2a、M2b、M2c、M2d、R^x And R^yAs formula (I) is defined above.

X is O；

R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：OH、F、Cl、N₃、NH₂And CN；

X is NH；

R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：OH、F、Cl、N₃、NH₂And CN；

Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt：

Wherein R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：F、Cl、OH、NH₂, CN and N₃；

One embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H and R²、R³And R⁴ As hereinbefore defined.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For F and R²、 R³And R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For Cl and R²、R³And R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, its Middle R¹For NH₂And R²、R³And R⁴As hereinbefore defined.

Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F and R³ And R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl and R³And R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, Wherein R¹For H, R²For OH and R³And R⁴As hereinbefore defined.Another embodiment also includes formula (II) compound, or which is pharmaceutically Acceptable salt, wherein R¹For H, R²For NH₂And R³And R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, Or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃And R³And R⁴As hereinbefore defined.

Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F, R³Choosing From CN and N₃, and R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, its Middle R¹For H, R²For F, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁴As determined above Justice.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F, R³It is selected from：First Base, ethyl and propyl group and R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or which is pharmaceutically acceptable Salt, wherein R¹For H, R²For F, R³It is selected from：Vinyl, acrylic and acetenyl and R⁴As hereinbefore defined.Another embodiment bag Include formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F, R³It is selected from：CH₂F、CHF₂And CH₂Cl and R⁴ As hereinbefore defined.

Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl, R³ It is selected from：CN and N₃And R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, Wherein R¹For H, R²For Cl, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁴Such as institute above Definition.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl, R³Choosing From：Methyl, ethyl and propyl group and R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or which pharmaceutically may be used The salt of acceptance, wherein R¹For H, R²For Cl, R³It is selected from：Vinyl, acrylic and acetenyl and R⁴As hereinbefore defined.Another reality The scheme of applying includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl, R³It is selected from：CH₂F、CHF₂With CH₂Cl and R⁴As hereinbefore defined.

Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH, R³ It is selected from：CN and N₃And R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, Wherein R¹For H, R²For OH, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁴Such as institute above Definition.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH, R³Choosing From：Methyl, ethyl and propyl group and R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or which pharmaceutically may be used The salt of acceptance, wherein R¹For H, R²For OH, R³It is selected from：Vinyl, acrylic and acetenyl and R⁴As hereinbefore defined.Another reality The scheme of applying includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH, R³It is selected from：CH₂F、CHF₂With CH₂Cl and R⁴As hereinbefore defined.

Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂, R³ It is selected from：CN and N₃And R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, Wherein R¹For H, R²For NH₂, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁴As above Defined.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂, R³ It is selected from：Methyl, ethyl and propyl group and R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or which is pharmaceutically Acceptable salt, wherein R¹For H, R²For NH₂, R³It is selected from：Vinyl, acrylic and acetenyl and R⁴As hereinbefore defined.It is another Embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂, R³It is selected from：CH₂F、 CHF₂And CH₂Cl and R⁴As hereinbefore defined.

Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃, R³ It is selected from：CN and N₃And R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, Wherein R¹For H, R²For N₃, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁴Such as institute above Definition.Another embodiment includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃, R³Choosing From：Methyl, ethyl and propyl group and R⁴As hereinbefore defined.Another embodiment includes formula (II) compound, or which pharmaceutically may be used The salt of acceptance, wherein R¹For H, R²For N₃, R³It is selected from：Vinyl, acrylic and acetenyl and R⁴As hereinbefore defined.Another enforcement Scheme includes formula (II) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃, R³It is selected from：CH₂F、CHF₂With CH₂Cl and R⁴As hereinbefore defined.

Another embodiment includes formula (III) compound：

Wherein：

R²For F, Cl, OH, NH₂, CN and N₃；

R⁴For H or following formula group：

Wherein W¹And W²It is each independently OH or Formulas I a group：

Wherein：

Each Y independently is key or O；

M is 0,1,2 or 3；

Each R^xFor H, halogen or OH；

Or

R⁴Selected from H and：

Wherein：

N ' is selected from：1st, 2,3 and 4；

R⁷It is selected from：C₁-C₈Alkyl ,-O-C₁-C₈Alkyl, benzyl ,-O- benzyls ,-CH₂-C₃-C₆Cycloalkyl ,-O-CH₂-C₃-C₆ Cycloalkyl and CF₃；

R⁸It is selected from：Phenyl, 1- naphthyls, 2- naphthyls,

R⁹Selected from H and CH₃；

R¹⁰Selected from H or C₁-C₆Alkyl；

R¹¹Selected from H, C₁-C₈Alkyl, benzyl, C₃-C₆Cycloalkyl and-CH₂-C₃-C₆Cycloalkyl.

Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F and R³ And R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For Cl And R³And R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R² For OH and R³And R⁴As hereinbefore defined.Another embodiment also includes formula (III) compound, or its pharmaceutically acceptable salt, Wherein R²For NH₂And R³And R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or which is pharmaceutically acceptable Salt, wherein R²For N₃And R³And R⁴As hereinbefore defined.

Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For F, R³It is selected from：CN And N₃And R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R² For F, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁴As hereinbefore defined.Another reality The scheme of applying includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For F, R³It is selected from：Methyl, ethyl and propyl group And R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For F, R³It is selected from：Vinyl, acrylic and acetenyl and R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or Its pharmaceutically acceptable salt, wherein R²For F, R³It is selected from：CH₂F、CHF₂And CH₂Cl and R⁴As hereinbefore defined.

Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For Cl, R³It is selected from： CN and N₃And R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For Cl, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁴As hereinbefore defined.It is another Embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For Cl, R³It is selected from：Methyl, ethyl and third Base and R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For Cl, R³It is selected from：Vinyl, acrylic and acetenyl and R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, Or its pharmaceutically acceptable salt, wherein R²For Cl, R³It is selected from：CH₂F、CHF₂And CH₂Cl and R⁴As hereinbefore defined.

Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For OH, R³It is selected from： CN and N₃And R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For OH, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁴As hereinbefore defined.It is another Embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For OH, R³It is selected from：Methyl, ethyl and third Base and R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For OH, R³It is selected from：Vinyl, acrylic and acetenyl and R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, Or its pharmaceutically acceptable salt, wherein R²For OH, R³It is selected from：CH₂F、CHF₂And CH₂Cl and R⁴As hereinbefore defined.

Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For NH₂, R³It is selected from： CN and N₃And R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For NH₂, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁴As hereinbefore defined.It is another Embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For NH₂, R³It is selected from：Methyl, ethyl and Propyl group and R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R² For NH₂, R³It is selected from：Vinyl, acrylic and acetenyl and R⁴As hereinbefore defined.Another embodiment includes formula (III) chemical combination Thing, or its pharmaceutically acceptable salt, wherein R²For NH₂, R³It is selected from：CH₂F、CHF₂And CH₂Cl and R⁴As hereinbefore defined.

Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For N₃, R³It is selected from： CN and N₃And R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For N₃, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁴As hereinbefore defined.It is another Embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For N₃, R³It is selected from：Methyl, ethyl and third Base and R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, or its pharmaceutically acceptable salt, wherein R²For N₃, R³It is selected from：Vinyl, acrylic and acetenyl and R⁴As hereinbefore defined.Another embodiment includes formula (III) compound, Or its pharmaceutically acceptable salt, wherein R²For N₃, R³It is selected from：CH₂F、CHF₂And CH₂Cl and R⁴As hereinbefore defined.

In each group described herein and embodiment, for formula (I), formula (II) and formula (III) compound, or its , there are other embodiments, wherein R in pharmaceutically acceptable salt¹、R²And R³As defined in respective group or embodiment and R⁴It is selected from：

Wherein：

N ' is selected from 1,2,3 and 4；

R⁷Selected from C₁-C₈Alkyl ,-O-C₁-C₈Alkyl, benzyl ,-O- benzyls ,-CH₂-C₃-C₆Cycloalkyl ,-O-CH₂-C₃-C₆Ring Alkyl and CF₃；

R⁸Selected from phenyl, 1- naphthyls, 2- naphthyls,

R⁹Selected from H and CH₃；

R¹⁰Selected from H or C₁-C₆Alkyl；

In each group described herein and embodiment, for formula (I), formula (II) and formula (III) compound, or its , also there are other embodiments, wherein R in pharmaceutically acceptable salt¹、R²And R³As defined in respective group or embodiment And R⁴It is selected from：

Wherein：

R⁷Selected from C₁-C₈Alkyl ,-O-C₁-C₈Alkyl, benzyl and-CH₂-C₃-C₆Cycloalkyl；And

R¹¹Selected from C₁-C₈Alkyl, benzyl, C₃-C₆Cycloalkyl and-CH₂-C₃-C₆Cycloalkyl.

In each group described herein and embodiment, for formula (I), formula (II) and formula (III) compound, or its , also there are other embodiments, wherein R in pharmaceutically acceptable salt¹、R²And R³As defined in respective group or embodiment And R⁴For following formula group：

Present invention also provides formula (IV) compound：

Wherein：

R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：F、Cl、OH、NH₂And N₃；

R³It is selected from：CN、N₃, methyl, ethyl, propyl group, vinyl, acrylic, acetenyl, CH₂F、CHF₂、CH₂Cl、CH₂SMe And CH₂OMe；And

R¹¹Selected from H, C₁-C₈Alkyl, benzyl, C₃-C₆Cycloalkyl and-CH₂-C₃-C₆Cycloalkyl；

Or its pharmaceutically acceptable salt.

One embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H and R²、R³And R¹¹ As hereinbefore defined.Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For F and R²、 R³And R¹¹As hereinbefore defined.Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For Cl and R²、R³And R¹¹As hereinbefore defined.Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, Wherein R¹For NH₂And R²、R³And R¹¹As hereinbefore defined.

Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F and R³ And R¹¹As hereinbefore defined.Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl and R³And R¹¹As hereinbefore defined.Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, Wherein R¹For H, R²For OH and R³With R11 as hereinbefore defined.Another embodiment also includes formula (IV) compound, or its pharmacy Upper acceptable salt, wherein R¹For H, R²For NH₂And R³And R¹¹As hereinbefore defined.Another embodiment includes formula (IV) chemical combination Thing, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃And R³And R¹¹As hereinbefore defined.

Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F, R³Choosing From：CN and N₃And R¹¹As hereinbefore defined.Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, Wherein R¹For H, R²For F, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R¹¹Such as institute above Definition.Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F, R³It is selected from： Methyl, ethyl and propyl group and R¹¹As hereinbefore defined.Another embodiment includes formula (IV) compound, or which is pharmaceutically acceptable Salt, wherein R¹For H, R²For F, R³It is selected from：Vinyl, acrylic and acetenyl and R¹¹As hereinbefore defined.Another embodiment Including formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F, R³It is selected from：CH₂F、CHF₂And CH₂Cl and R¹¹As hereinbefore defined.

Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl, R³ It is selected from：CN and N₃And R¹¹As hereinbefore defined.Another embodiment includes formula (IV) compound, or which is pharmaceutically acceptable Salt, wherein R¹For H, R²For Cl, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R¹¹As above Text is defined.Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl, R³ It is selected from：Methyl, ethyl and propyl group and R¹¹As hereinbefore defined.Another embodiment includes formula (IV) compound, or which is pharmaceutically Acceptable salt, wherein R¹For H, R²For Cl, R³It is selected from：Vinyl, acrylic and acetenyl and R¹¹As hereinbefore defined.It is another Embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl, R³It is selected from：CH₂F、CHF₂ And CH₂Cl and R¹¹As hereinbefore defined.

Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH, R³ It is selected from：CN and N₃And R¹¹As hereinbefore defined.Another embodiment includes formula (IV) compound, or which is pharmaceutically acceptable Salt, wherein R¹For H, R²For OH, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R¹¹As above Text is defined.Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH, R³ It is selected from：Methyl, ethyl and propyl group and R¹¹As hereinbefore defined.Another embodiment includes formula (IV) compound, or which is pharmaceutically Acceptable salt, wherein R¹For H, R²For OH, R³It is selected from：Vinyl, acrylic and acetenyl and R¹¹As hereinbefore defined.It is another Embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH, R³It is selected from：CH₂F、CHF₂ And CH₂Cl and R¹¹As hereinbefore defined.

Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂, R³ It is selected from：CN and N₃And R¹¹As hereinbefore defined.Another embodiment includes formula (III) compound, or which is pharmaceutically acceptable Salt, wherein R¹For H, R²For NH₂, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R¹¹Such as It is defined above.Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂, R³It is selected from：Methyl, ethyl and propyl group and R¹¹As hereinbefore defined.Another embodiment includes formula (IV) compound, or its Pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂, R³It is selected from：Vinyl, acrylic and acetenyl and R¹¹As determined above Justice.Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂, R³It is selected from： CH₂F、CHF₂And CH₂Cl and R¹¹As hereinbefore defined.

Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃, R³ It is selected from：CN and N₃And R¹¹As hereinbefore defined.Another embodiment includes formula (IV) compound, or which is pharmaceutically acceptable Salt, wherein R¹For H, R²For N₃, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R¹¹As above Text is defined.Another embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃, R³ It is selected from：Methyl, ethyl and propyl group and R¹¹As hereinbefore defined.Another embodiment includes formula (IV) compound, or which is pharmaceutically Acceptable salt, wherein R¹For H, R²For N₃, R³It is selected from：Vinyl, acrylic and acetenyl and R¹¹As hereinbefore defined.It is another Embodiment includes formula (IV) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃, R³It is selected from：CH₂F、CHF₂ And CH₂Cl and R¹¹As hereinbefore defined.

Another embodiment includes formula (V) compound：

Wherein：

R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：F、Cl、OH、NH₂And N₃；

R³It is selected from：CN、N₃, methyl, ethyl, propyl group, vinyl, acrylic, acetenyl, CH₂F、CHF₂、CH₂Cl、CH₂SMe And CH₂OMe；

R⁹Selected from H and CH₃；

R¹⁰Selected from H or C₁-C₆Alkyl；With

Or its pharmaceutically acceptable salt.

One embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H and R²、R³And R¹¹ As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For F and R²、 R³、R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, its Middle R¹For Cl and R²、R³、R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or which pharmaceutically may be used The salt of acceptance, wherein R¹For NH₂And R²、R³、R⁹、R¹⁰And R¹¹As hereinbefore defined.

Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F and R³、 R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹ For H, R²For Cl and R³、R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or which pharmaceutically may be used The salt of acceptance, wherein R¹For H, R²For OH and R³、R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment is also changed including formula (V) Compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂And R³、R⁹、R¹⁰And R¹¹As hereinbefore defined.Another enforcement Scheme includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃And R³、R⁹、R¹⁰And R¹¹As above Defined.

Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F, R³Choosing From：CN and N₃And R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or which is pharmaceutically acceptable Salt, wherein R¹For H, R²For F, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁹、R¹⁰ And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F, R³It is selected from：Methyl, ethyl and propyl group and R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) chemical combination Thing, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F, R³It is selected from：Vinyl, acrylic and acetenyl and R⁹、R¹⁰With R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R² For F, R³It is selected from：CH₂F、CHF₂And CH₂Cl and R⁹, R¹⁰And R¹¹As hereinbefore defined.

Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl, R³Choosing From：CN and N₃And R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or which is pharmaceutically acceptable Salt, wherein R¹For H, R²For Cl, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁹、 R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl, R³It is selected from：Methyl, ethyl and propyl group and R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) Compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl, R³It is selected from：Vinyl, acrylic and acetenyl and R⁹、 R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl, R³It is selected from：CH₂F、CHF₂And CH₂Cl and R⁹、R¹⁰And R¹¹As hereinbefore defined.

Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH, R³Choosing From：CN and N₃And R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or which is pharmaceutically acceptable Salt, wherein R¹For H, R²For OH, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁹、 R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH, R³It is selected from：Methyl, ethyl and propyl group and R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) Compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH, R³It is selected from：Vinyl, acrylic and acetenyl and R⁹、 R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH, R³It is selected from：CH₂F、CHF₂And CH₂Cl and R⁹, R¹⁰And R¹¹As hereinbefore defined.

Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂, R³ It is selected from：CN and N₃And R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or which can pharmaceutically connect The salt received, wherein R¹For H, R²For NH₂, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹ For H, R²For NH₂, R³It is selected from：Methyl, ethyl and propyl group and R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂, R³It is selected from：Vinyl, acrylic and acetenyl And R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂, R³It is selected from：CH₂F、CHF₂And CH₂Cl and R⁹、R¹⁰And R¹¹As hereinbefore defined.

Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃, R³Choosing From：CN and N₃And R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or which is pharmaceutically acceptable Salt, wherein R¹For H, R²For N₃, R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl and CH₂OMe and R⁹, R¹⁰ And R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃, R³It is selected from：Methyl, ethyl and propyl group and R⁹、R¹⁰And R¹¹As hereinbefore defined.Another embodiment includes formula (V) chemical combination Thing, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃, R³It is selected from：Vinyl, acrylic and acetenyl and R⁹、R¹⁰With R¹¹As hereinbefore defined.Another embodiment includes formula (V) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R² For N₃, R³It is selected from：CH₂F、CHF₂And CH₂Cl and R⁹、R¹⁰And R¹¹As hereinbefore defined.

Present invention also provides formula (VI) compound：

Wherein：

X is selected from：O, S and NH；

R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：F、Cl、OH、NH₂, CN and N₃；And

Or its pharmaceutically acceptable salt.

Present invention also provides formula (VII) compound：

Wherein：

R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：F、Cl、OH、NH₂, CN and N₃；With

Or its pharmaceutically acceptable salt.

Present invention also provides formula (VIII) compound：

Wherein：

R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：F、Cl、OH、NH₂, CN and N₃；With

Or its pharmaceutically acceptable salt.

Present invention also provides formula (IX) compound：

Wherein：

R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：F、Cl、OH、NH₂, CN and N₃；With

Or its pharmaceutically acceptable salt.

One embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H and R²And R³Such as It is defined above.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For F and R²And R³ As hereinbefore defined.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For Cl and R² And R³As hereinbefore defined.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For NH₂ And R²And R³As hereinbefore defined.

Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F and R³ As hereinbefore defined.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl and R³As hereinbefore defined.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH and R³As hereinbefore defined.Another embodiment also includes formula (IX) compound, or its pharmaceutically acceptable salt, Wherein R¹For H, R²For NH₂And R³As hereinbefore defined.Another embodiment includes formula (V) compound, or which is pharmaceutically acceptable Salt, wherein R¹For H, R²For N₃And R³As hereinbefore defined.

Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F and R³ It is selected from：CN and N₃.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F And R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl, CH₂SMe and CH₂OMe.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F and R³It is selected from：Methyl, ethyl and propyl group.Another reality The scheme of applying includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F and R³It is selected from：Vinyl, third Thiazolinyl and acetenyl.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For F And R³It is selected from：CH₂F、CHF₂And CH₂Cl。

Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl and R³ It is selected from：CN and N₃.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl And R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl, CH₂SMe and CH₂OMe.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl and R³It is selected from：Methyl, ethyl and propyl group.It is another Embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For Cl and R³It is selected from：Vinyl, Acrylic and acetenyl.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R² For Cl and R³It is selected from：CH₂F、CHF₂And CH₂Cl。

Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH and R³ It is selected from：CN and N₃.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH And R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl, CH₂SMe and CH₂OMe.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH and R³It is selected from：Methyl, ethyl and propyl group.It is another Embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For OH and R³It is selected from：Vinyl, Acrylic and acetenyl.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R² For OH and R³It is selected from：CH₂F、CHF₂And CH₂Cl。

Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂And R³It is selected from：CN and N₃.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂And R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl, CH₂SMe and CH₂OMe.Another embodiment bag Include formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂And R³It is selected from：Methyl, ethyl and propyl group. Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For NH₂And R³It is selected from：Second Thiazolinyl, acrylic and acetenyl.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹ For H, R²For NH₂And R³It is selected from：CH₂F、CHF₂And CH₂Cl。

Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃And R³ It is selected from：CN and N₃.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃ And R³It is selected from：Methyl, ethyl, propyl group, vinyl, acrylic, acetenyl, CH₂SMe and CH₂OMe.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃And R³It is selected from：Methyl, ethyl and propyl group.It is another Embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R²For N₃And R³It is selected from：Vinyl, Acrylic and acetenyl.Another embodiment includes formula (IX) compound, or its pharmaceutically acceptable salt, wherein R¹For H, R² For N₃And R³It is selected from：CH₂F、CHF₂And CH₂Cl。

Present invention also provides single embodiment, which includes the compound of formula (Xa), formula (Xb) or formula (Xc), or its Pharmaceutically acceptable salt：

Wherein X, R¹、R²、R³And R^aAs formula (I) is defined and R above¹²It is selected from optionally by a NH in each case₂Base The C that group replaces₁-C₆Alkyl.

In the above-mentioned each embodiment represented with formula (Xa), formula (Xb) or formula (Xc), there are other embodiments, its bag The compound, or its pharmaceutically acceptable salt are included, wherein X is S, R¹²It is selected from optionally by a NH in each case₂Base The C that group replaces₁-C₆Alkyl and R¹、R²、R³And R^aAs formula (I) is defined above.

In the above-mentioned each embodiment represented with formula (Xa), formula (Xb) or formula (Xc), there are other embodiments, its bag Compound, or its pharmaceutically acceptable salt are included, wherein X is S, R¹For H and R²、R³And R^aAs formula (I) is defined above.

In the above-mentioned each embodiment represented with formula (Xa), formula (Xb) or formula (Xc), there are other embodiments, its bag Compound, or its pharmaceutically acceptable salt are included, wherein X is S, R¹For H, R¹²For C₂-C₄Alkyl or-C (NH₂)-C₂-C₄Alkyl and R²、R³And R^aAs formula (I) is defined above.

In the above-mentioned each embodiment represented with formula (Xa), formula (Xb) or formula (Xc), there are other embodiments, its bag Compound, or its pharmaceutically acceptable salt are included, wherein X is S, R¹For H, R¹²It is selected from：Ethyl, isopropyl ,-C (NH₂)-second Base ,-C (NH₂)-isopropyl and R²、R³And R^aAs formula (I) is defined above.

Other single embodiments include any following formula: compound, or its pharmaceutically acceptable salt：

Wherein, in each independent embodiment, R²、R³、R^aAs formula (I) is defined above.

Term halogen and halogen refer to the halogen atom selected from F, Cl, Br and I.

" azido " refers to azido group, i.e. group-N₃.Term " n " used herein refers to selected from 2,3,4,5,6,7, 8th, 9,10,11,12,13,14,15,16,17,18,19 and 20 integer.

Term " haloalkyl " used herein refers to alkyl as defined herein, wherein one or more hydrogen atoms Base replacement is optionally substituted by halogen each.For example, (C₁-C₆) haloalkyl is (C₁-C₆) alkyl, wherein one or more hydrogen atoms are It is optionally substituted by halogen base replacement.Such scope includes a halogenic substituent on alkyl group to the complete halogen of alkyl group Change.

Term " (C used herein_1-n) haloalkyl ", wherein n is integer, individually or with another moiety combinations, it is intended to table Show the alkyl group with 1-n carbon atom as defined above, wherein one or more hydrogen atoms are each optionally substituted by halogen base and replace Generation.Wherein n is 2 (C_1-n) haloalkyl example include, but not limited to chloromethyl, chloroethyl, Dichloroethyl, bromomethyl, Bromoethyl, dibromoethyl, methyl fluoride, difluoromethyl, trifluoromethyl, fluoro ethyl and two fluoro ethyls.This group may be based on phase Close halogen and be described as " (C_1-n) chlorine alkyl ", " (C_1-n) bromine alkyl " or " (C_1-n) fluoroalkyl ".

Term " (C used herein_1-n) alkyl ", wherein n is integer, individually or with another moiety combinations, it is intended to expression contains There are non-annularity, the straight or branched alkyl of 1-n carbon atom.“(C_1-8) alkyl " include, but not limited to methyl, ethyl, propyl group (n-pro-pyl), butyl (normal-butyl), 1- Methylethyls (isopropyl), 1- methyl-propyls (sec-butyl), 2- methyl-propyl (isobutyls Base), 1,1- dimethyl ethyls (tert-butyl group), amyl group, hexyl, heptyl and octyl group.Abbreviation Me represents methyl group；Et represents ethyl Group, Pr represent propyl group, and iPr represents 1- Methylethyl groups, and Bu represents that butyl group and tBu represent 1,1- dimethyl second Base group.

Term " alkyl " refers to the hydrocarbon containing primary, secondary or tertiary atom.For example, alkyl can have 1-20 carbon atom (i.e., (C₁-C₂₀) alkyl), 1-10 carbon atom (that is, (C₁-C₁₀) alkyl), 1-8 carbon atom (that is, (C₁-C₈) alkyl) or 1-6 carbon Atom (that is, (C₁-C₆Alkyl).The example of suitable alkyl includes, but not limited to methyl (Me ,-CH₃), ethyl (Et ,- CH₂CH₃), 1- propyl group (n- Pr, n-pro-pyl ,-CH₂CH₂CH₃), 2- propyl group (i- Pr, isopropyl ,-CH (CH₃)₂), 1- butyl (n- Bu, normal-butyl ,-CH₂CH₂CH₂CH₃), 2- methyl isophthalic acids-propyl group (i- Bu, isobutyl group ,-CH₂CH(CH₃)₂), 2- butyl (sIt is-Bu, secondary Butyl ,-CH (CH₃)CH₂CH₃), 2- methyl-2-propyls (t- Bu, the tert-butyl group ,-C (CH₃)₃), 1- amyl groups (n-pentyl ,- CH₂CH₂CH₂CH₂CH₃), 2- amyl groups (- CH (CH₃)CH₂CH₂CH₃), 3- amyl groups (- CH (CH₂CH₃)₂), 2- methyl -2- butyl (- C (CH₃)₂CH₂CH₃), 3- methyl -2- butyl (- CH (CH₃)CH(CH₃)₂), 3- methyl isophthalic acids-butyl (- CH₂CH₂CH(CH₃)₂), 2- first Base -1- butyl (- CH₂CH(CH₃)CH₂CH₃), 1- hexyl (- CH₂CH₂CH₂CH₂CH₂CH₃), 2- hexyls (- CH (CH₃) CH₂CH₂CH₂CH₃), 3- hexyls (- CH (CH₂CH₃)(CH₂CH₂CH₃)), 2- methyl -2- amyl groups (- C (CH₃)₂CH₂CH₂CH₃), 3- first Base -2- amyl groups (- CH (CH₃)CH(CH₃)CH₂CH₃), 4- methyl -2- amyl groups (- CH (CH₃)CH₂CH(CH₃)₂), 3- methyl -3- penta Base (- C (CH₃)(CH₂CH₃)₂), 2- methyl -3- amyl groups (- CH (CH₂CH₃)CH(CH₃)₂), 2,3- dimethyl -2- butyl (- C (CH₃)₂CH(CH₃)₂), 3,3- dimethyl -2- butyl (- CH (CH₃)C(CH₃)₃With octyl group (- (CH₂)₇CH₃)." alkyl " is also referred to With by two monovalent radicals obtained by two hydrogen atoms are removed from same one or two different carbon atoms of parent alkane The saturation at center, side chain or straight-chain hydrocarbons group.For example, alkyl group can have 1-10 carbon atom (that is, (C₁-C₁₀) alkyl) or 1-6 carbon atom (that is, (C₁-C₆) alkyl) or 1-3 carbon atom (that is, (C₁-C₃) alkyl).Typical alkyl includes, but does not limit In methylene (- CH₂-), 1,1- ethyls (- CH (CH₃) -), 1,2- ethyl (- CH₂CH₂-), 1,1- propyl group (- CH (CH₂CH₃)-)、 1,2- propyl group (- CH₂CH(CH₃) -), 1,3- propyl group (- CH₂CH₂CH₂-), 1,4- butyl (- CH₂CH₂CH₂CH₂-) etc..

" thiazolinyl " is with least one unsaturation site (i.e. carbon-to-carbon sp comprising primary, secondary or tertiary carbon atom²Double bond) Straight or branched hydrocarbon.For example, alkenyl group can have 2-20 carbon atom (that is, C₂-C₂₀Thiazolinyl), 2-8 carbon atom (that is, C₂- C₈Thiazolinyl) or 2-6 carbon atom (that is, C₂-C₆Thiazolinyl).The example of suitable alkenyl group include, but not limited to ethylidene or Vinyl (- CH=CH₂), pi-allyl (- CH₂CH=CH₂), cyclopentenyl (- C₅H₇) and 5- hexenyl (- CH₂CH₂CH₂CH₂CH= CH₂)。

Term " (C used herein_2-n) thiazolinyl ", wherein n is integer, individually or with another moiety combinations, it is intended to expression contains There are unsaturation, acyclic straight or the straight chain group of two to n carbon atom, wherein at least two carbon atom passes through double bond each other Bonding.The example of this group includes, but not limited to vinyl, 1- acrylic, 2- acrylic and 1-butylene base.Unless in addition Refer to, term " (C_2-n) thiazolinyl " be interpreted as covering possible single stereoisomer, including but not limited to (E) and (Z) isomery Body and its mixture.As (C_2-n) alkenyl group it is substituted when, it should be appreciated that unless otherwise mentioned, otherwise will to carry hydrogen originally former Replacement on its any carbon atom of son so that the replacement will obtain chemically stable compound, such as those skilled in the art Those recognized.

" alkynyl " is with least one unsaturated site (i.e. three keys of carbon-to-carbon sp) containing primary, secondary or tertiary carbon atom Straight or branched hydrocarbon.For example, alkynyl can have 2-20 carbon atom (that is, C₂-C₂₀Alkynyl), 2-8 carbon atom (that is, C₂-C₈Alkynes Base) or 2-6 carbon atom (that is, C₂-C₆Alkynyl).The example of suitable alkynyl include, but not limited to acetenyl (- C ≡ CH), third Alkynyl (- CH₂C ≡ CH) etc..

Term " (C used herein_2-n) alkynyl ", wherein n be integer, individually or with another moiety combinations, it is intended to represent Containing the unsaturation of two to n carbon atom, acyclic straight or branched group, wherein at least two carbon atom by three key that This bonding.Wherein n is that the example of 4 group includes, but not limited to acetenyl, 1- propinyls, 2-propynyl and ethyl acetylene Base.As (C_2-n) alkynyl group it is substituted when, it should be appreciated that unless otherwise noted, be otherwise script by carry hydrogen atom its Replacement on meaning carbon atom so that the replacement will obtain chemically stable compound, as those skilled in the art recognize Those.

Term " aryl " used herein refers to that single aromatic ring is bicyclic or multi-ring, and for example, aryl can have 6 to 20 carbon Atom, 6 to 14 carbon atoms or 6 to 12 carbon atoms.Aryl includes that phenyl or the ortho-condensed with about 9-14 atom are double Ring or polycyclic moiety, wherein at least one ring are (such as with one or more aryl or carbocyclic fused aryl) of fragrance.This It is kind bicyclic or it is multi-ring can be optionally by one or more (such as 1,2 or 3) oxo groups in bicyclic or multi-ring any carbocyclic ring Part replaces.It should be understood that as defined above bicyclic or multi-ring junction point can be in the optional position of the ring, including the ring Aryl or isocyclic part.Typical aryl includes, but not limited to phenyl, indenyl, naphthyl, 1,2,3,4- tetralyls, anthryl Deng.

" aryl " includes that the aromatic hydrocarbon with 6-10 carbon atom is monocyclic or bicyclic, including phenyl ring and naphthalene nucleus.Substituted virtue Base includes that the aromatic hydrocarbon with 6-10 carbon atom is monocyclic or bicyclic, including phenyl ring and naphthalene nucleus, including 1- naphthyls, 2- naphthyl rings, And the homocyclic aromatic monocyclic groups containing 6 carbon atoms, which can further be fused to second 5- or 6- units carbon ring group, institute It can be fragrant, saturation or undersaturated to state second 5- or 6- units carbon ring group, including indanyl, indenyl, tetralyl With dihydronaphthalene basic ring, wherein each aromatic ring replaced independently selected from following substituent group by 0,1,2 or 3：Halogen ,-OH ,- CN、-NO₂、-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、C₁-C₆Alkyl, C₁-C₆Alkoxyl and-CF₃。

" aryl alkyl " refers to alkyl as defined herein, and one of them hydrogen atom with carbon atom bonding is by this Shen Aromatic yl group (that is, aryl-alkyl-part) that please be described is substituted.The alkyl of " aryl alkyl " is usually 1-6 carbon atom (i.e. aryl (C₁-C₆) alkyl).Aryl alkyl includes, but not limited to benzyl, 2- phenyl second -1- bases, 1- phenyl propyl- 1- bases, naphthalene Ylmethyl, 2- naphthyl second -1- bases etc..

Term " aryl-(C used herein_1-n) alkyl-", wherein n is integer, individually or with another moiety combinations, it is intended to The alkyl with 1-n carbon atom defined herein is represented, itself is replaced by aryl as defined above.Aryl-(C_1-n) Alkyl-example include, but not limited to phenyl methyl (benzyl), 1- phenylethyls, 2- phenylethyls and phenyl propyl.Work as virtue Base-(C_1-n) alkyl-substituted when, it should be appreciated that unless otherwise mentioned, otherwise substituent group may be connected to aryl or its moieties Or both so that the replacement will obtain chemically stable compound, as recognized by those skilled in the art.

" aryl alkyl " used herein refers to formula-(CH₂)_qThe part of-Y, wherein q are independently to select in each case From following integer：1st, 2,3,4,5 or 6 and " Y " is phenyl ring or naphthalene nucleus, each taken independently selected from following by 0,1,2 or 3 Replace for base：Halogen ,-OH ,-CN ,-NO₂、-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、C₁-C₆Alkyl, C₁-C₆Alcoxyl Base and-CF₃。

Term " heterocycle " is synonymous and unless otherwise mentioned, is otherwise referred to 3,4,5,6,7,8,9 or 10 ring originals Son (it is C that wherein 1,2,3 or 4 annular atom is independently selected from the hetero atom and all remaining annular atoms of N, O and S) it is monocyclic And condensed-bicyclic, saturation or part unsaturation ring.In one embodiment, the heterocyclic group has 5,6,9 or 10 Individual annular atom, wherein 1,2 or 3 annular atoms are independently selected from the hetero atom of N, O and S.The heterocyclic group includes 2 wherein In all of embodiment of individual or multiple hetero atoms (N, O and S), the hetero atom is probably identical or different.Wherein Compound of formula I is included in all embodiments of 2 or multiple heterocyclic groups, and the heterocyclic group can be identical or different 's.The example of heterocyclic group includes but is not limited to oxirane base, azetidinyl, oxetanyl, thia ring fourth Alkyl (thietanyl), furyl, tetrahydrofuran base, thienyl, tetrahydro-thienyl, thio-oxidizing tetrahydro-thienyl, pyrroles Base, pyrrolinyl, pyrrolidinyl, dioxolane Ji, oxazolidinyl, oxazolyl, isoxazolyls, thiazolyl, isothiazolyl, Imidazole radicals, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazole radical, pyranose, dihydro pyrrole Mutter base, THP trtrahydropyranyl, pyridine radicals, dihydropyridine base, piperidyl, dioxane base, morpholinyl, dithiane base, thio Morpholinyl, pyridazinyl, pyrimidine radicals, pyrazinyl, piperazinyl, triazine radical, indolizine base (indolizinyl), indyl, iso-indoles Base, oxyindole base (oxindolyl), indolinyl, benzofuranyl, dihydro benzo furyl, isobenzofuran-base, benzene Bithiophene base, indazolyl, benzimidazolyl, benzoxazole quinoline base, benzoxazolyl, benzoisoxazole base, benzothiazolyl, benzene And triazolyl, benzopyranyl, purine radicals, quinolizinyl, quinolyl, isoquinolyl, tetrahydric quinoline group, tetrahydro isoquinolyl, ten Hydrogen quinolyl, octahydro isoquinolyl, cinnolines base, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, pteridyl, sulfur naphthyl (thianaphthalenyl) etc..Heterocyclic group can be combined by any available ring carbon or ring hetero atom (such as N).It is respectively " miscellaneous Cyclic group " or " heterocycle " can be replaced independently selected from following substituent group by 0,1,2 or 3：Halogen ,-OH ,-CN ,-NO₂、- NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、C₁-C₆Alkyl, C₁-C₆Alkoxyl and-CF₃。

Term cycloalkyl refers to cyclic aliphatic group.Cycloalkyl in the application can be with the carbon number table on their rings Show, for example " C₃-C₄Cycloalkyl " refers to the cycloalkyl ring with 3 or 4 carboatomic ring atoms or " C₃-C₆Cycloalkyl " represents with 3, 4th, the cycloalkyl ring of 5 or 6 carboatomic ring atoms, i.e. cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl ring.

Term " carbocyclic ring " or " carbocylic radical " refer to 3-8 carbon atom as monocyclic or multi-ring loop systems saturation (i.e., Cycloalkyl) or unsaturated (for example, the cycloalkenyl group, cycloalkadienyl etc.) ring in part.In one embodiment, the carbocyclic ring is to include Monocyclic (i.e. (the C of 3-6 ring carbon₃-C₆) carbocyclic ring).Carbocyclic ring includes multi-ring carbocyclic ring, and which has 7-12 carbon atom as bicyclic and many Up to about 20 carbon atoms as multi-ring, on condition that the monocyclic of the maximum of multi-ring carbocyclic ring is 7 carbon atoms.Term " spiral shell bicyclic carbocyclic " Carbocyclic ring bicyclic system is referred to, wherein the ring of the bicyclic system is connected to single carbon atom (such as spiropentane, spiral shell [4,5] decane, spiral shell [4.5] decane etc.).Term " fused bicyclic carbocycle " refers to carbocyclic ring bicyclic system, wherein the ring of the bicyclic system is connected to two Individual adjacent carbon atom, such as bicyclic [4,5], [5,5], [5,6] or [6,6] system or 9 or 10 annular atoms line up it is bicyclic [5, 6] or [6,6] system (such as decahydronaphthalene, nor- sabinane (norsabinane), nor- carane (norcarane)).Term " bridging-bicyclic carbocycle " refers to carbocyclic ring bicyclic system, wherein the ring of the bicyclic system is connected to two non-conterminous carbon (for example Norcamphane, bicyclic [2.2.2] octane etc.)." carbocyclic ring " or " carbocylic radical " are optionally by one or more (such as 1,2 or 3) Oxo group replaces.The non-limiting examples of monocycle carbocyclic ring include the amyl- 1- thiazolinyls of cyclopropyl, cyclobutyl, cyclopenta, 1- rings, 1- The amyl- 2- thiazolinyls of ring, the amyl- 3- thiazolinyls of 1- rings, cyclohexyl, 1- hexamethylene -1- thiazolinyls, 1- hexamethylene -2- thiazolinyls, 1- hexamethylene -3- thiazolinyls, ring Hex- 1,3- dialkylene, suberyl, cycloheptenyl, cycloheptyl -1,3- dialkylenes, cycloheptyl -1,4- dialkylenes, cyclooctyl and cyclo-octene Basic ring.

Each carbocylic radical can be replaced independently selected from following substituent group by 0,1,2 or 3：Halogen ,-OH ,-CN ,-NO₂、- NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、C₁-C₆Alkyl, C₁-C₆Alkoxyl and-CF₃。

Term " heteroaryl " used herein refers to single aromatic ring or multiple condensed ring.The term is included on ring about 1-6 The individual carbon atom and about 1-4 heteroatomic single aromatic ring selected from oxygen, nitrogen and sulfur.The sulfur and nitrogen-atoms can also be with oxidised forms Exist, as long as the ring is fragrant.The ring includes but is not limited to pyridine radicals, pyrimidine radicals, oxazolyls or furyl.The term may be used also Including many carbocyclic fused ring systems (such as the loop systems comprising 2 or 3 rings), wherein as defined herein heteroaryl can with one or Multiple or heteroaryl (such as naphthyridinyl), carbocyclic ring (such as 5,6,7,8- tetrahydric quinoline groups) or aryl (such as indazolyl) condense with Form many condensed ring.This many condensed ring are optionally by one or more (such as 1, the 2 or 3) oxo bases on the isocyclic part of the condensed ring Group replaces.It should be appreciated that the junction point of many condensed ring of heteroaryl as defined above can be in the optional position of the ring, including the ring Heteroaryl, aryl or isocyclic part.Exemplary heteroaryl includes but is not limited to pyridine radicals, pyrrole radicals, pyrazinyl, pyrimidine Base, pyridazinyl, pyrazolyl, thienyl, indyl, imidazole radicals, oxazolyls, thiazolyl, furyl, oxadiazolyls, thiadiazolyl group, Quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolyl, 5,6,7,8- tetrahydrochysenes are different Quinolyl, benzofuranyl, benzimidazolyl and thianaphthenyl (thianaphthenyl).

Each heteroaryl can be replaced independently selected from following substituent group by 0,1,2 or 3：Halogen ,-OH ,-CN ,-NO₂、- NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、C₁-C₆Alkyl, C₁-C₆Alkoxyl and-CF₃。

" heteroaryl alkyl " refers to alkyl as defined herein, one of them hydrogen atom quilt sheet with carbon atom bonding The described heteroaryl of application substitutes (that is, heteroaryl-alkyl-part).The alkyl of " heteroaryl alkyl " is usually 1-6 carbon atom (i.e. heteroaryl (C₁-C₆) alkyl).Heteroaryl alkyl includes, but are not limited to heteroaryl-CH₂-, heteroaryl-CH (CH₃)-, heteroaryl Base-CH₂CH₂-, 2- (heteroaryl) second -1- bases etc., wherein " heteroaryl " partly includes any heteroaryl described herein. It will further be appreciated by those of ordinary skill in the art that the heteroaryl can be connected to the heteroaryl alkane by carbon-carbon bond or carbon-heteroatom bond The moieties of base, on condition that gained group is chemically stable.It is first that the example of heteroaryl alkyl includes, but not limited to, e.g. 5- The heteroaryl of sulfur-bearing, oxygen and/or nitrogen, such as benzothiazolylmethyl, 2- thiazolyl second -1- bases, imidazolyl methyl, oxazole ylmethyl, Thiadiazolyl group methyl etc., the heteroaryl of 6- units sulfur-bearing, oxygen and/or nitrogen, such as pyridylmethyl, pyridizyl methyl, pyrimidine radicals Methyl, pyrazinyl-methyl etc..

The hetero-aromatic ring of each heteroaryl alkyl can be replaced independently selected from following substituent group by 0,1,2 or 3：Halogen ,- OH、-CN、-NO₂、-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、C₁-C₆Alkyl, C₁-C₆Alkoxyl and-CF₃。

Any formula or structure that the application is given, including compound of formula I and its pharmaceutically acceptable salt, are also intended to represent Unmarked form and isotope labelled form compound or its salt.Isotope-labeled compound or its salt has this Shen The structure described by formula that please be given, except one or more atoms are by with the atom generation for selecting atomic mass or mass number Replace.The isotopic example that may be incorporated into the compounds of this invention includes the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, but It is not limited to²H (deuterium, D),³H (tritium),¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I.Different isotope-labeled are sent out Bright compound or its salt, for example, mix radiosiotope (for example³H、¹³C and¹⁴C) those.This isotope-labeled chemical combination Thing or its salt can be used for metabolism research, Reaction kinetics research, detection or imaging technique (such as PET (positron emission tomography) (PET) or single photon emission computed topography (SPECT), including medicine or substrate tissue distribution measuring) or experimenter The radiation treatment of (such as people).

Present invention additionally comprises compound of formula I and its pharmaceutically acceptable salt, wherein 1-n hydrogen quilt being connected with carbon atom Deuterium is substituted, and wherein n is the hydrogen number in the molecule.This compound can show the resistance increased to metabolism and therefore when administration Can be used for improving the half-life of compound of formula I or its pharmaceutically acceptable salt during to mammal.See, e.g., Foster, " Deuterium Isotope Effects in Studies of Drug Metabolism ", Trends Pharmacol.Sci.5(12):524-527(1984).Such compound is synthesized by mode well known in the art, for example, adopt The parent material for having been substituted by deuterium with wherein one or more hydrogen.

The therapeutic compounds of the deuterium-labelled or replacement of the present invention can (drug metabolism and medicine be for power with the DMPK for improving Learn) property, which is related to distribution, metabolism and excretion (ADME).Being replaced by heavier isotope (such as deuterium) can be due to higher generation Thank stability (Half-life in vivo for for example increasing), reduce volume requirements and/or improvement therapeutic index and provide certain Treatment advantage.¹⁸The compound of F labellings can be used for PET or SPECT researchs.Isotope-labeled the compounds of this invention and its prodrug The isotope labeling reagent that can generally pass through to be readily able to obtain replaces nonisotopic labels reagent, by implementing hereinafter described to react Formula or embodiment and the method disclosed in preparing are prepared.It should be understood that deuterium in this application is considered as compound of formula I And its substituent group in pharmaceutically acceptable salt.

The concentration of this heavier isotope (especially deuterium) can be defined with isotope enrichment factor.The present invention's In compound, any stable isotope that the arbitrary atom for specific isotope is intended to indicate that the atom is not specifically designated.Unless Illustrate in addition, when a position be specifically designated for " H " or " hydrogen " when, the position is understood to natural abundance isotope groups Into hydrogen.Therefore, in the compound or its salt of the present invention, the arbitrary atom for being specially designated as deuterium (D) is intended to indicate that deuterium.

Pharmaceutical preparation

Present invention also provides pharmaceutical preparation, which includes formula (I) compound of pharmacy effective dose or which is pharmaceutically acceptable Salt, solvate and/or ester and pharmaceutically acceptable carrier or excipient.Single pharmaceutical preparation is additionally provided, each Formula comprising pharmacy effective dose (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) compound and sheet The particular compound or its pharmaceutically acceptable salt, solvate and/or ester and pharmaceutically acceptable load of application embodiment Body or excipient.

The application compound is prepared together with conventional carrier and excipient, the carrier and excipient will be according to common realities Trample teaching options.Tablet will be containing excipient, fluidizer, filler, binding agent etc..Aqueous formulation is with sterile form system It is standby, and when intending to deliver by non-oral administration, which is typically isotonic.All of preparation will optionally contain figuration Agent, such as those described in " Handbook of Pharmaceutical Excipients " (1986).Excipient includes Ascorbic acid and other antioxidants, chelating agen (such as EDTA), carbohydrate (such as glucosan), hydroxyalkylcellulose Element, hydroxyalkyl methyl cellulose, stearic acid etc..The pH scopes of the preparation are about 3 to about 11, when typically about 7 to 10.

Although active component can be administered alone, preferably provide as pharmaceutical preparation.Veterinary is with people's Preparation includes at least one active component defined above and one or more acceptable carrier and optional other treatment The extra therapeutic component of composition, particularly those discussed herein.The carrier must be " acceptable ", mean with The other compositions of preparation are compatible and be physiologically harmless for its receiver.

The preparation includes those suitable for aforementioned route of administration.The preparation can be conveniently presented in unit dosage form simultaneously And can be prepared by any means known to pharmaceutical field.Technology and preparation can be generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA).The method include by it is described activity into The carrier-bound step divided and constitute one or more auxiliary element.Generally, the preparation by by the active component with Liquid-carrier or solid carrier in small, broken bits or both are uniform and closely combine, and then if desired the finished product molding Prepare.

The preparation for being suitable to oral administration can be present as discrete unit, such as capsule, cachet or tablet, and which each contains The active component of scheduled volume；As powder or granule；As solution or suspension in aqueouss or on-aqueous liquid；Or as water The oily liquid emulsion of bag or water-in-oil liquid Emulsion.The active component is alternatively arranged as the administration of pill, electuary or paste.

Tablet is prepared by compression or plastotype, optionally together with one or more auxiliary element.Compressed tablets can pass through By the active component (such as powder or granule) of the stranglehold liquid form in suitable machine, optionally with binding agent, profit Lubrication prescription, inert diluent, preservative, surfactant or dispersant are prepared.Molded tablet can be by suitable Machine in molding prepared with the mixture of the powder active ingredient of inert liquid diluent moistening.The tablet is optionally It is coated or indentation, and is optionally formulated to provide the slow or control release of active component.

For the infection of eyes or other outside organizations (such as oral cavity and skin), the preparation is preferably as topical ointment Or cream is applied, which contains a certain amount of active component, and for example, 0.075-20%w/w (includes that scope, 0.1% to 20%, increases Measure the active component for 0.1%w/w, such as 0.6%w/w, 0.7%w/w etc.), preferred 0.2-15%w/w and most preferably 0.5- 10%w/w.When active component is formulated into ointment, then the active component can adopt paraffin or water-miscible ointment base. Or, the active component can be with Oil-in-water emulsifiable paste substrate preparation into emulsifiable paste.

If desired, the water of the emulsifiable paste matrix mutually may include, for example, at least polyhydric alcohol of 30%w/w, i.e., with two Or the alcohol of multiple hydroxyls, such as Propylene Glycol, butyl- 1,3- glycol, Mannitol, Sorbitol, glycerol and Polyethylene Glycol (include PEG And its mixture 400).The topical formulations can be ideally comprised strengthens active component by skin or other involved areas The compound for absorbing or permeating.The example of this skin penetration enhancer includes the analog of dimethyl sulfoxide and correlation.

The oil phase of Emulsion can be made up of in known manner known composition.Although the phase only can include emulsifying agent (or Referred to as emulgent), but which is ideally comprising the mixture that at least one emulsifying agent is both oily or fatty with fat and oily.It is preferred that Ground, hydrophilic emulsifier are included together with the lipophilic emulsifier worked as stabilizer.Preferably comprising oil and Fat.So-called emulsifing wax is constituted together with or without the emulsifying agent of stabilizer and wax constitute together with oil ＆ fat it is so-called Emulsifying ointment base, its formed cream preparation oiliness dispersion phase.

Include suitable for the emulgent and emulsion stabilizer of preparation60、80th, hexadecanol octadecanol is mixed Compound, benzylalcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

Selection for the suitable oil ＆ fat of preparation is to be based on to realize desired cosmetic property.The emulsifiable paste Ying You Elect the non-oily with suitable consistency, non-staining and rinsable product as to avoid leaking from pipe or other containers.Can make With straight or branched, unitary or binary alkyl ester, such as two different adipate esters, Standamul 7061, the third of coconut fatty acid Diol diesters, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, Palmic acid 2- Octyl Nitrites or Know the mixture of the branched ester for Crodamol CAP, last three is preferred ester.These can according to required property individually or It is applied in combination.Or, using high-melting-point lipid, such as White soft paraffin and/or liquid paraffin or other mineral oil.

The application pharmaceutical preparation includes and one or more pharmaceutically acceptable carrier or excipient and optional other Therapeutic agent combination together.Pharmaceutical preparation containing the active component can be adapted for the arbitrary form for being expected medication. When for orally use when, can prepare for example, tablet, containing tablet, lozenge, aqueouss or oil-based suspension, dispersible powder or Grain, Emulsion, hard capsule or soft capsule, solution, syrup or elixir.Composition for oral use can be according to known in the art Any means for preparing pharmaceutical composition are prepared and said composition containing one or more reagent, including sweetener, can be adjusted Taste agent, coloring agent and preservative, to provide agreeable to the taste preparation.Containing what is mixed with nontoxic pharmaceutically acceptable excipient The tablet of active component can be acceptance, and the excipient is suitable to prepare tablet.These excipient can be, for example, inertia Diluent, such as Calcium Carbonate or sodium carbonate, Lactose, calcium phosphate or sodium phosphate；Granulating agent and disintegrating agent, such as corn starch or sea Alginic acid；Binding agent, such as starch, gelatin or arabic gum；And lubricant, such as magnesium stearate, stearic acid or Talcum.Tablet can To be uncoated or can be coated by known technology (including microencapsulation), to postpone disintegrate in the gastrointestinal tract and suction It is attached, so as to provide the continuous action of longer time.For example, time delay material can be used, such as it is single hard individually or together with wax Glycerol or distearin.

The preparation for orally using can also be hard gelatin capsule, wherein the active component and inert solid diluent (example Such as calcium phosphate or Kaolin) mixing, or can be Perle, wherein the active component (is such as spent with water or oil medium Oil generation, liquid paraffin or olive oil) mixing.

Aqueous suspension contains and is suitable to prepare the active substance that the excipient of aqueous suspension mixes.This excipient bag Include suspension emulsion, such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidine Ketone, Tragacanth and Radix Acaciae senegalis and dispersant or wetting agent, such as naturally occurring phospholipid (for example, lecithin), thiazolinyl The condensation of the condensation product (for example, Myrj 45), oxirane and long-chain fat race alcohol of oxide and fatty acid Product (for example, heptadecaethylene oxycetanol), oxirane are produced with the condensation derived from fatty acid and the partial ester of hexitan Thing (for example, polyoxyethylene 20 sorbitan monooleate).The aqueous suspension can also contain one or more preservative, example Such as ethylparaben or P-hydroxybenzoic acid n-propyl, one or more coloring agent, one or more flavoring agent and Plant or various sweeteners, such as sucrose or saccharin.

Oil suspension can be by suspension active component in vegetable oil (such as Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois) In or in mineral oil (such as liquid paraffin) preparing.Oral suspensionses can contain thickening agent, such as Cera Flava, hard paraffin or spermaceti Alcohol.Sweetener (such as those described above) and flavoring agent can be added to provide agreeable to the taste oral formulations.These compositionss can be by adding Enter antioxidant (such as ascorbic acid) to preserve.

Be suitable to by adding water prepare aqueous suspension dispersible powder and granule there is provided with dispersion or wetting agent, outstanding Active component in the mixture of Emulsion and one or more preservative.Suitable dispersion or wetting agent and suspension emulsion are with public above As a example by those opened.Also there may be other excipient, such as sweetener, flavoring agent and coloring agent.

Pharmaceutical composition can also be in the form of oil-in-water emulsion.Oil phase can be vegetable oil, such as olive oil or Oleum Arachidis hypogaeae semen, ore deposit Thing oil (such as liquid paraffin) or their mixture.Suitable emulsifying agent includes naturally occurring natural gum (such as Arabic tree Glue and Tragacanth), naturally occurring phospholipid (such as soybean lecithin), ester or partial ester derived from fatty acid and hexitan Condensation product (such as polyoxyethylene sorbitan of (such as sorbitan monooleate) and these partial esters and oxirane Monoleate).Emulsion can also contain sweetener and flavoring agent.Syrup and elixir can be with sweetener such as glycerol, Sorbitol or sugarcanes Sugar is prepared.This preparation can also contain demulcent, preservative, flavoring agent or coloring agent.

Pharmaceutical composition can be in sterile injectable preparation or intravenous formulations such as sterile injectable aqueouss or oleaginous suspension Form.This suspensoid can be according to known technology using those the suitable dispersants or wetting agent and suspending agent having already mentioned above Prepare.Sterile injectable preparation or intravenous formulations are alternatively the nothing in nontoxic, the acceptable diluent of parenteral or solvent Bacterium Injectable solution or suspension, such as solution in 1,3 butylene glycol or be prepared into freeze-dried powder.It is adoptable acceptable Supporting agent and solvent have water, Ringer's mixture and isotonic sodium chlorrde solution.Additionally, generally can using sterile fixed oil as solvent or Suspension media.To this purpose, any gentle fixing oil can be adopted, including the monoglyceride or dialycerides of synthesis.This Outward, generally can be using fatty acid, such as Oleic acid in the preparation of injection.

Can with carrier material be combined to produce single formulation active component amount with the main body treated and specifically to Medicine pattern and it is different.For example, the slow releasing preparation for being administered orally to the mankind can contain about 1-1000mg with it is suitable and convenient The active substance of the carrier material allotment of amount, wherein the carrier material can be about 5 to about 95% (weight of total composition:Weight Amount).Described pharmaceutical composition can be formulated as providing the amount for being easy to measure to be administered.For example, it is intended to which the aqueouss of venoclysises are molten Liquid can contain the active component/milliliter solution of about 3 to 500 μ g, to occur with the suitable volumes of the speed of about 30mL/hr Infusion.

The preparation for being adapted to be locally applied to eye also includes eye drop, and wherein active component is dissolved or suspended in suitable carrier In, in particular in the aqueous solvent of active component.Active component is preferably with 0.5 to 20%, advantageously 0.5 to 10% and spy It is not that the concentration of about 1.5%w/w is present in such preparation.

The preparation for being adapted to be locally applied in mouth is included in flavouring base material typically sucrose and arabic gum or Tragacanth Lozenge comprising active component；It is soft comprising active component in inertia base material such as gelatin and glycerol or sucrose and arabic gum Lozenge；With the collutory comprising active component in suitable liquid-carrier.

Formulations for rectal administration can be provided as suppository, and which has the suitable base comprising such as cocoa butter or salicylate Material.

The preparation of suitable intrapulmonary or nose administration has for example in 0.1 to 500 micrometer range, and such as 0.5,1,30,35 Deng particle size, its pass through per nasal road quickly suction or by oral inhalation to reach alveolar sac.Suitable preparation bag Include the aqueouss or oily solution of active component.The preparation of suitable aerosol or dry powder administration can prepare according to conventional methods and can be with Other therapeutic agents, it is as described below to be used for before this treating or prevent the compound of pneumonitis viruss subfamily infection to be delivered together.

Another embodiment provide be suitable to treat the infection of pneumonitis viruss subfamilies and it is potential with bronchiolitises it is new, The inhalable composition of effectively, safe, non-stimulated and physical compatibility, its contained I-IX compound, or which can pharmaceutically connect The salt received.Preferred pharmaceutically acceptable salt is inorganic acid salt, including hydrochlorate, hydrobromate, sulfate or phosphate, because Less lung may be caused to stimulate for them.Preferably, inhalable formulations are delivered to bronchus in the aerosol comprising granule Interior space, the granule is with about 1 to about 5 μm of mass median aerodynamic diameter (MMAD).Preferably, Formulas I-IX chemical combination Thing is formulated as using aerosol apparatus, pressurised metered dose inhalers (pMDI) or Diskuses (DPI) with Aerosol delivery.

The non-limiting examples of aerosol apparatus include being atomized, spray, ultrasound wave, pressurization, vibration porous plate or equivalent aerosol apparatus, Including using self adaptation Aerosol delivery technology (Denyer, J. aerosol medicine Pulmonary Drug Delivery 2010,23Supp 1, S1-S10) those aerosol apparatus.Liquid solution is broken into gas using air pressure by jet nebulizer Mist agent droplet.Ultrasonic sprayer is worked by piezoquartz, and which is by liquid shear into little aerosol droplets.Pressure atomization system System forces solution to pass under pressure through fine pore to generate aerosol droplets.Porous plate equipment utilization fast vibration is vibrated by liquid Body stream cuts into suitable droplet size.

In preferred embodiments, for the preparation of atomization using can be by the fogging into required of Formulas I-IX compounds The aerosol apparatus of the granule of MMAD, by the Aerosol delivery of the granule comprising MMAD mainly between about 1 μm to about 5 μm to a gas Space in pipe.For optimal treatment effectiveness and in order to avoid upper respiratory tract and systemic side effects, most of aerosolizations Grain should not have greater than about 5 μm of MMAD.If aerosol contains granules of a large amount of MMAD more than 5 μm, then the granule will The amount of the medicine for being delivered to inflammation and bronchoconstriction position in lower respiratory tract is reduced in being deposited on epithelium healing.If aerosol Less than about 1 μm of MMAD, then what is breathed out in exhalation process during the granule has the air for remaining suspended in suction and subsequently becomes Gesture.

When being prepared according to the present processes and deliver, the aerosol formulation for atomization will be to pneumonitis viruss subfamily sense Dye site delivery be enough to the Formulas I-IX compounds of the treatment effective dose for treating the pneumonitis viruss subfamily infection.The medicine of administration Amount must be adjusted reflecting the delivery efficiency of the Formulas I-IX compounds for the treatment of effective dose.In preferred embodiments, aqueouss Aerosol formulation is allowed about extremely with the combination of atomization, injection, pressurization, vibration porous plate or ultrasonic nebulizer (depending on aerosol apparatus) Few 20 to about 90%, the Formulas I-IX compounds of normally about 70% dosage are delivered in air flue.In preferred embodiments, extremely The reactive compound of few about 30 to about 50% is delivered.It is highly preferred that the reactive compound of about 70 to about 90% is delivered.

In another embodiment, Formulas I-IX compounds or its pharmaceutically acceptable salt are passed with dry inhalable powders Send.The compound uses dry powder or metered-dose inhaler with dry powder formulations Intrabronchial administration, effectively to deliver the thin of compound Granule is to endobronchial space.For by the delivering of DPI, processed or from solution by grinding spray drying, critical fluids Precipitate and Formulas I-IX compounds are processed into into granules of the MMAD mainly between about 1 μm to about 5 μm.MMAD can be produced between about 1 μ Between m to about 5 μm, the medium milling of particle size, jet grinding and spray-drying installation and operation are well known in the art. In one embodiment, before the granule of required size is processed into, excipient is added in the Formulas I-IX compounds.Another In one embodiment, excipient is blended to help the dispersion of drug particles, such as by using Lactose with the granule of required size As excipient.

Particle size determination equipment well known in the art is carried out.For example, multistage Anderson cascade impactors or other conjunctions Sign equipment in suitable method, such as the 601st chapter of American Pharmacopeia as the aerosol in quantitative and Diskuses is clearly carried Those for arriving.

In another preferred embodiment of the present, Formulas I-IX compounds use device (such as Diskuses or other dry powder point It is in bulk to put) delivered with dry powder.The non-limiting examples of Diskuses and device include US5,458,135；US5,740,794； US5775320；US5,785,049；US3,906,950；US4,013,075；US4,069,819；US4,995,385；US5, 522,385；US4,668,218；US4,667,668；Those disclosed in US4,805,811 and US5,388,572.Dry powder is sucked Device has two kinds of major designs.One kind is designed as metering device, and the reservoir of wherein medicine is placed in device and patient is by dose Medicine be added in suction chamber.It is designed as the device measure in factory for second, each of which individual dose is fabricated in Individually in container.Two systems each depend on medicine be configured to little particle that MMAD is 1 μm to about 5 μm and be usually directed to compared with Big excipient granule, the such as but not limited to co-formulation of Lactose.Drug powder is placed in suction chamber (measured by device or It is quantitative by breaking factory) and the inspiratory flow of patient powder quick is out gone forward side by side in entrance cavity from device.Powder path Non-laminar flow characteristic causes excipient-medicine group dimer decomposition, and the block of big excipient granule causes them in throat rear impacts, And less drug particles are deposited in lung dearly.In preferred embodiments, Formulas I-IX compounds, or which pharmaceutically may be used The salt of acceptance, is delivered with dry powder using any type of Diskuses as described in the present application, wherein the dry powder (not including appointing What excipient) MMAD mainly in the range of 1 μm to about 5 μm.

In another embodiment, Formulas I-IX compounds are delivered with dry powder using metered-dose inhaler.Metered-dose inhaler and dress The non-limiting examples put include US5,261,538；US5,544,647；US5,622,163；US4,955,371；US3,565, 070；Those disclosed in US3,361306 and US6,116,234.In preferred embodiments, Formulas I-IX compounds, or its medicine Acceptable salt on, is delivered with dry powder using metered-dose inhaler, wherein the MMAD of the dry powder (not including any excipient) It is main in the range of about 1-5 μm.

The preparation for being suitable to vagina administration can be carried with pessary, tampon, cream, gel, paste, foam or spray agent For which also contains carrier suitable as known in the art in addition to the active component.

The preparation for being suitable to parenteral includes aqueouss and non-aqueous sterile injection solution, and which can contain antioxidant, delay The solute for rushing liquid, antibacterial and making said preparation isotonic with the blood of expected receiver；And aqueouss and non-aqueous sterile suspension, its Suspension emulsion and thickening agent can be included.

Preparation is provided with unit dose or multi-dose container, such as sealed ampoule and bottle, and it is dry to can be stored in freezing Under the conditions of dry (lyophilizing), it is only necessary to adding at once sterile liquid carrier (such as water) to inject using front.Extemporaneous injection is molten Liquid and suspension are prepared according to the species of previously described sterilized powder, granule and tablet.Preferred unit dose formulations Be the active component containing daily dose as described above or unit day sub-doses or its appropriate fraction those.

It should be understood that in addition to composition specifically mentioned above, preparation can be comprising the preparation class in this area with regard to being considered Other conventional reagents of type, are for example suitable for those contained flavoring agents of oral administration.

Animal medicinal composition is additionally provided, which includes at least one active component and its veterinary drug carrier as defined above.

Veterinary drug carrier is the material of the purpose for applying said compositions can be for solid, liquid or gas material, its Originally be inert or veterinary applications in it is acceptable and compatible with the active component.These animal medicinal compositions can orally, stomach It is parenteral or be administered by the approach arbitrarily needed for other.

The application compound be used for controlled-release pharmaceutical formulation is provided, its contain compound described in one or more as activity into Divide (" controlled release preparation "), wherein controlling and adjusting the release of the active component to allow relatively low medicine frequency or improve given The pharmacokineticss or toxicity characteristic of active component.

The effective dose of active component is prophylactically to make at least dependent on the property of disease for the treatment of, toxicity, compound With (relatively low-dose) or to countermeasure activity infections, delivering method and pharmaceutical preparation, and will be used by clinician Routine dose is incremented by research to determine.Which is it is contemplated that for about 0.0001 to about 100mg/kg body weight/day；Normally about 0.01 to about 10mg/kg body weight/days；More generally, about 0.01 to about 5mg/kg body weight/day；Most commonly, about 0.05 to about 0.5mg/kg body weight/ My god.For example, the adult of body weight about 70kg day candidate dosage will in the range of 1mg to 1000mg, preferred 5mg and Between 500mg, and it can be in the form of single dose or multiple dose.

Route of administration

Compound described in one or more (the application is referred to as active component) is by suitable to disease to be treated any Approach is administered.Suitable approach include orally, rectum, nose, lung, local (including cheek and Sublingual), vagina and parenteral (wrap Include subcutaneous, intramuscular, intravenouss, Intradermal, intrathecal and epidural) etc..It should be understood that preferred approach can be with the disease of such as receiver And it is different.It is orally bioavailable and Orally-administrable that the advantage of the application compound is which.

Combination treatment

Compositionss also can be applied in combination with other active components.For pneumonitis viruss subfamily virus infection treatment, preferably Ground, described other active therapeutic agents are infected to pneumonitis viruss subfamily virus, and particularly respiratory syncytial virus infection is active.This The non-limiting examples of a little other active therapeutic agents are ribavirin, palivizumab, do not tie up pearl monoclonal antibody, RSV-IGIVMEDI-557, A-60444 (also referred to as RSV604), MDT-637, BMS-433771, ALN-RSV0, ALX- 0171 and its mixture.

The infection of many pneumonitis viruss subfamily viruses is respiratory tract infection.Therefore, for treating respiratory symptom and infection Other active therapeutic agents of sequela can be applied in combination with Formulas I-IX compounds.The preferred oral administration of the other therapeutic agents is logical Cross and be directly sucked in administration.For example, share with Formulas I-IX compound groups in treatment viral respiratory tract infection other it is preferred its His therapeutic agent includes, but not limited to bronchodilator and corticosteroid.

Glucocorticoid, initially as treating asthma nineteen fifty introduce (Carryer, Journal of Allergy, 21,282-287,1950), which remains, and this disease is most effective and the therapy of continuous and effective, but their mechanism of action is not yet Understand completely (Morris, J.Allergy Clin.Immunol., 75 (1Pt) 1-13,1985).Unfortunately, oral glucose cortex Hormonotherapy with serious adverse side effect, for example central obesity, hypertension, glaucoma, glucose intolerance, it is white in Barrier forms acceleration, bone mineral and is lost in and psychological impact, all these all to limit which as the use of long-term treatment agent (Goodman and Gilman, the 10th edition, 2001).One solution of systemic side effects is directly to deliver to inflammation part Steroid medicine.Suction has been developed with corticosteroid (ICS) to alleviate the serious side effects of oral steroid.Can be with Formulas I-IX The non-limiting examples of the corticosteroid that compound is applied in combination are dexamethasone, dexamethasone sodium phosphate, fluorometholone, acetic acid Fluorometholone, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisone, triamcinolone, Qu An Nai De, betamethasone, beclomethasone dipropionate, first Po Songlong, fluocinolone (fluocinolone), fluocinolone acetone (fluocinolone acetonide), flunisolide, fluocortin -21- butyl compounds, flumetasone, flumetasone pivalate, cloth Desonide, halobetasol propionate, momestasone furoate, Fluticasone Propionate, ciclesonide；Or its pharmaceutically acceptable salt.

It also is used as combining with Formulas I-IX compounds by other antiinflammatories that antiinflammatory cascade mechanism works treating disease The other therapeutic agents of toxicity respiratory tract infection.Apply " anti-inflammatory signal transduction adjusting control agent " (being referred to as AISTM in this application), such as phosphorus Acid diesters enzyme inhibitor (such as PDE-4, PDE-5 or PDE-7 specific inhibitor), transcription factor inhibitor (for example, pass through IKK suppresses blocking NF κ B) or kinase inhibitor (for example, block P38MAP, JNK, PI3K, EGFR or Syk) be turned off inflammation Logical method, because the common cell inner gateway of these small molecule targeting limited quantities：It is key point to antiinflammatory Results Those signal transduction pathways (referring to P.J.Barnes, 2006 summary).These nonrestrictive other therapeutic agents include：5- (2,4- dilquoro-phenogies) -1- isobutyl group -1H- indazole -6- formic acid (2- dimethylarnino-ethyls)-amide (P38Map kinases Inhibitor ARRY-797)；3- cyclo propyl methoxy-N- (3,5- Dichloro-pendin -4- bases) -4- difluoro-methoxies-Benzoylamide (PDE-4 inhibitor roflumilasts)；4- [2- (3- cyclopentyloxy -4- methoxyphenyls) -2- phenyl-ethyl groups]-pyridine (PDE- 4 inhibitor C DP-840)；N- (bis- chloro- 4- pyridine radicals of 3,5-) -4- (difluoro-methoxy) -8- [(methyl sulphonyl) amino] -1- Dibenzofurans Methanamide (PDE-4 inhibitor Oglemilast)；N- (3,5- Dichloro-pendin -4- bases) -2- [1- (4- fluorine benzyls Base) -5- hydroxyl -1H- indol-3-yls] -2- oXo-acetamides (PDE-4 inhibitor AWD 12-281)；8- methoxyl group -2- trifluoros Methyl-quinoline -5- formic acid (bis- chloro- 1- epoxides-pyridin-4-yls of 3,5-)-amide (PDE-4 inhibitor Sch351591)；4-[5- (4- fluorophenyls) -2- (4- Methanesulfinyl-phenyls) -1H- imidazol-4 yls]-pyridine (P38 inhibitor SB-203850)；4- (P38 suppresses [4- (4- fluoro-phenyls) -1- (3- phenyl-propyl group) -5- pyridin-4-yl -1H- imidazoles -2- bases]-butyl- 3- alkynes -1- alcohol Agent RWJ-67657)；4- cyano group -4- (3- cyclopentyloxies -4- methoxyl groups-phenyl)-naphthenic acid 2- diethylaminos-second Ester (the 2- diethyl-Ethyl ester prodrugs of cilomilast, PDE-4 inhibitor)；(the chloro- 4- fluorophenyls of 3-)-[7- methoxyl group -6- (3- Quinoline -4- bases-propoxyl group)-quinazoline -4- bases]-amine (gefitinib, EGFR inhibitor)；With 4- (4- thyl-piperazin -1- Ji Jia Base) (imatinib, EGFR suppress-N- [4- methyl-3- (4- pyridin-3-yls-pyrimidine -2 --amino)-phenyl]-Benzoylamide Agent).

Comprising suction beta-2-adrenoreceptor agonists bronchodilator (such as formoterol, albuterol or sand It is also Mei Teluo) suitable with the combination of Formulas I-IX compounds, but nonrestrictive can be used to treat respiratory virus infection Combination.

Suction beta-2-adrenoreceptor agonists bronchodilator (such as formoterol or salmaterol) and ICS Combination be also used for treating both bronchoconstriction and inflammation and (use respectivelyWith).Comprising these The combination of ICS and beta-2-adrenoreceptor agonists and the combination of Formulas I-IX compounds are also suitable and nonrestrictive Can be used to treat the combination of respiratory virus infection.

For the treatment or prevention of pulmonary branches airway constriction, anticholinergic has potential purposes simultaneously, therefore, as with formula The other therapeutic agents that I-IX compounds combine to treat viral respiratory tract infection.These anticholinergics include, but not limited to The antagonist of muscarinic receptor (particularly M3 hypotypes), shows in the control of its cholinergic tensity in people COPD Therapeutic effect (Witek, 1999)；1- { 4- hydroxyl -1- [tri--(4- fluoro-phenyls)-propionos of 3,3,3-]-pyrrolidine -2- carbonyls Base }-pyrrolidine -2- formic acid (1- methyl-pi -4- ylmethyls)-amide；3- [3- (2- diethylaminos-acetoxyl group) -2- Phenyl-propionyl epoxide] -8- isopropyl -8- methyl -8- azonias-bicyclic [3.2.1] octane (the sweet ammonia of ipratropium-N, N- Diethyl phthalate)；1- cyclohexyl -3,4- dihydro -1H- isoquinolin -2- formic acid 1- aza-bicyclos [2.2.2] oct-3-yl ester (Suo Li That is pungent)；2- hydroxymethyl -4- methanesulfinyl -2- Phenyl-butyric acid 1- aza-bicyclos [2.2.2] oct-3-yl esters are (auspicious to cut down support Ester)；2- { 1- [2- (2,3- Dihydro-benzofuran -5- bases)-ethyl]-pyrrolidin-3-yl } -2,2- diphenyl-acetamides (reach Fei Naxin)；4- cycloheximide -1- base -2,2- diphenvl-butyramides (Bu Zhuo, Buzepide)；7- [3- (2- diethylaminos- Acetoxyl group) -2- phenyl-propionyl epoxides]-three ring [3.3.1.02,4] of -9- ethyl -9- methyl -3- oxa- -9- azonias Nonane (oxitropium methylbromide-N, N- glycine diethylester)；7- [2- (2- diethylaminos-acetoxyl group) -2,2- two-thiophene -2- Base-acetoxyl group] -9,9- dimethyl -3- oxa- -9- azonias-three ring [3.3.1.02,4] nonane (tiotropium bromide-N, N- Glycine diethylester)；Dimethylamino-acetic acid 2- (3- diisopropylaminoethyls -1- phenyl-propyl group) -4- methyl-phenyl esters (support Special Luoding-N, N- glycine dimethyl ester)；3- [4,4- pair-(4- fluoro-phenyls) -2- oxo-imidazolidin -1- bases] -1- methyl isophthalic acids - (2- oxo -2- pyridines -2- bases-ethyl)-pyrrolidine；1- [1- (the fluoro- benzyls of 3-)-piperidin-4-yl] -4,4- pair-(4- is fluoro- Phenyl)-imidazolidin-2-one；1- cyclooctyl -3- (3- methoxyl group -1- aza-bicyclos [2.2.2] oct-3-yls) -1- phenyl -propyl- 2- alkynes -1- alcohol；3- [2- (2- diethylaminos-acetoxyl group) two-thiophene of -2,2- -2- bases-acetoxyl group] -1- (3- benzene oxygen Base-propyl group) -1- azonias-bicyclic [2.2.2] octane (aclidinium bromide (Aclidinium)-N, N- glycine diethylester)；Or (2- diethylaminos-acetoxyl group)-two-thiophene -2- bases-acetic acid 1- methyl isophthalic acids-(2- phenoxy groups-ethyl)-piperidin-4-yl Ester.

Both infection that Formulas I-IX compounds also can combine to treat respiratory tract infection with mucolytic agent and symptom.It is molten viscous The nonrestrictive example of protein agent is ambroxol.Similarly, the Formulas I-IX compounds can be combined with resolving sputum agent and be exhaled to treat Inhale both infection and the symptom of road infection.The nonrestrictive example of resolving sputum agent is guaifenesin.

The hypertonic saline of atomization be used for improve with consumptive small airway instant and long-term removing (Kuzik, J.Pediatrics 2007,266).Formulas I-IX compounds also can be combined with atomization hypertonic saline, particularly when pneumonitis viruss are sub- When coe virus infects concurrent bronchiolitises.The combination of Formulas I-IX compounds and hypertonic saline can also comprising it is discussed above other Reagent.In one embodiment, hypertonic saline is atomized using about 3%.

Can with single formulation by any compound extra with one or more active therapeutic agent combine come while or Patient is administered to successively.The combination treatment can be administered as simultaneously or sequentially scheme.When applying successively, the combination Can be administered with two or more times administration.

The administering drug combinations of the application compound and one or more other active therapeutic agent typically refer to compound with one kind Or be administered while various other active therapeutic agents or successively, so as to compound and one or more other work of therapeutically effective amount Property therapeutic agent is present in the body of patient.

Before or after administering drug combinations are included in one or more other active therapeutic agent that unit dose is administered, administration is single The compound of position dosage, for example, is being administered several seconds of one or more other active therapeutic agent, several minutes or in a few hours The compound is administered.For example, the compound of unit dose can be administered first, and unit dose is administered within several seconds or several minutes then One or more other active therapeutic agent of amount.Or, one or more other therapeutic agents of unit dose can be administered first, so The compound of unit dose is administered afterwards within several seconds or several minutes.In some cases, it can be possible to need unit dose is administered first Compound, one or more of unit dose other work is then administered after the time of a few hours (for example, 1-12 hour) Property therapeutic agent.In other cases, it may be necessary to one or more other active therapeutic agent of unit dose is administered first, then The application compound of unit dose is administered after the time of a few hours (for example, 1-12 hour).

Combination treatment can provide " synergism " and " cooperative effect ", i.e., the effect for obtaining when active component is used together More than the effect sum that the compound generation is used alone.Collaboration effect can be obtained when active component is applied as follows Should：(1) co-formulation is in a kind of combination preparation and is administered simultaneously or delivers；(2) by being used as single preparation alternately or Parallel delivering；Or (3) are by some other schemes.When being delivered with rotational therapy, when the compound is for example with single piece Agent, pill or capsule or by the different injections in independent syringe come single administration or delivering when can obtain collaboration effect Really.Generally, each active component of effective dose during rotational therapy, successively, i.e., is continuously administered, and in combination treatment In, two or more active component of effective dose are administered together.Synergistic corrosion virus effect refers to the single chemical combination more than combination The antiviral effect of the pure additive effect of expection of thing.

Also in another embodiment, this application provides a kind of side that the virus infection of pneumonitis viruss subfamily is treated in people Method, methods described include formula (I) compound or pharmaceutically acceptable salt to people's drug treatment effective dose, solvate and/ Or its ester.The independent method that the virus infection of pneumonitis viruss subfamily is treated in people is additionally provided, respectively includes to people's drug treatment having The formula (II) of effect property pharmacy effective dose, formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) are changed One of particular compound of compound or the embodiment of the present application or its pharmaceutically acceptable salt, solvate and/or ester and pharmacy Upper acceptable carrier or excipient.

In another embodiment, this application provides by the outer of formula (I) compound to people's drug treatment effective dose Raceme, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, non-crystalline forms, hydration The method that thing or solvate or its pharmaceutically acceptable salt or ester are infected the pneumonitis viruss subfamily for the treatment of the people.

The independent method that the infection of pneumonitis viruss subfamily is treated in the people for having this to need is additionally provided, each method is included to institute State the formula (II) of people's drug treatment effective dose, formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) racemic modification of compound, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, One of particular compound of non-crystalline forms, hydrate or solvate or the embodiment of the present application or which is pharmaceutically acceptable Salt, solvate and/or ester.

Also in another embodiment, this application provides a kind of side that human respiratory syncytial virus' infection is treated in people Method, methods described include formula (I) compound or pharmaceutically acceptable salt, solvate to people's drug treatment effective dose And/or its ester.

Also in another embodiment, this application provides a kind of side that human respiratory syncytial virus' infection is treated in people Method, the method include formula (I) compound or pharmaceutically acceptable salt to people's drug treatment effective dose, solvate and/ Or its ester and at least one extra active therapeutic agent.

The independent method that human respiratory syncytial virus' infection is treated in the people for having this to need is additionally provided, each method includes Formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) to people's drug treatment effective dose, One of particular compound of formula (IX) compound or the embodiment of the present application or its pharmaceutically acceptable salt, solvate and/or Ester.

The independent method that human respiratory syncytial virus' infection is treated in the people for having this to need is additionally provided, each method includes Formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) to people's drug treatment effective dose, One of particular compound of formula (IX) compound or the embodiment of the present application or its pharmaceutically acceptable salt, solvate and/or Ester and at least one extra active therapeutic agent.

The independent method that human respiratory syncytial virus' infection is treated in the people for having this to need is additionally provided, wherein the people Also undergoing bronchiolitises, each method include formula (I) to people's drug treatment effective dose, formula (II), formula (III), The particular compound of formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) compound or the embodiment of the present application it One or its pharmaceutically acceptable salt, solvate and/or ester.

The independent method that human respiratory syncytial virus' infection is treated in the people for having this to need is additionally provided, wherein the people It is experienced by pneumonia, each method includes formula (I) to people's drug treatment effective dose, formula (II), formula (III), formula (IV), formula (V), one of particular compound of formula (VI), formula (VII), formula (VIII), formula (IX) compound or the embodiment of the present application or its medicine Acceptable salt, solvate and/or ester on.

Additionally providing improves the independent method of respiratory symptom, each side in the people for undergoing human respiratory syncytial virus' infection Method includes formula (I) to people's drug treatment effective dose, formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), one of particular compound of formula (VIII), formula (IX) compound or the embodiment of the present application or which is pharmaceutically acceptable Salt, solvate and/or ester.

May include nasal obstruction or rhinorrhea, cough the respiratory symptom in the people of respiratory syncytial virus infection is undergone Cough, wheezing, sneeze, rapid breathing or dyspnea, asphyxia, bronchiolitises and pneumonia.

An embodiment is additionally provided, which includes formula (I) compound or its pharmaceutically acceptable salt, solvate And/or ester is in the medicine for being used for treating the infection of pneumonitis viruss subfamily virus or respiratory syncytial virus infection in people is prepared Purposes.

An embodiment is additionally provided, which includes formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), one of particular compound of formula (VIII), formula (IX) compound or the embodiment of the present application or which is pharmaceutically acceptable Salt, solvate and/or ester are being prepared in people for treating the infection of pneumonitis viruss subfamily virus or respiratory syncytial virus sense Purposes in the medicine of dye.

Present invention also provides pharmaceutical preparation, which includes formula (I) compound of pharmacy effective dose or which is pharmaceutically acceptable Salt, solvate and/or ester and pharmaceutically acceptable carrier or excipient.Present invention also provides pharmaceutical preparation, its bag Formula containing pharmacy effective dose (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) chemical combination One of particular compound of thing or the embodiment of the present application or its pharmaceutically acceptable salt, solvate and/or ester and pharmaceutically Acceptable carrier or excipient.

Present invention also provides pharmaceutical preparation, which includes formula (I) compound of pharmacy effective dose or which is pharmaceutically acceptable Salt, solvate and/or ester and pharmaceutically acceptable carrier or excipient and pharmacy effective dose it is at least one extra Active therapeutic agent.Present invention also provides pharmaceutical preparation, formula (II) which includes pharmacy effective dose, formula (III), formula (IV), formula (V), one of particular compound of formula (VI), formula (VII), formula (VIII), formula (IX) compound or the embodiment of the present application or its medicine On, acceptable salt, solvate and/or ester and pharmaceutically acceptable carrier or excipient and pharmacy effective dose be at least A kind of extra active therapeutic agent.

Single embodiment is additionally provided, which includes formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), one of particular compound of formula (VII), formula (VIII), formula (IX) compound or the embodiment of the present application or its pharmaceutically may be used The salt of acceptance, solvate and/or ester, which is used to the infection of pneumonitis viruss subfamily virus or respiratory syncytial virus to be treated in people Infection.

Single embodiment is additionally provided, which includes formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), one of particular compound of formula (VII), formula (VIII), formula (IX) compound or the embodiment of the present application or its pharmaceutically may be used The salt of acceptance, solvate and/or ester, which is used as medicine.

Single embodiment is additionally provided, which includes that manufacturing the pneumonitis viruss subfamily virus for being intended to treat people infects or exhale Inhale road syncytial virus infection medicine method, methods described particularly in using formula (I), formula (II), formula (III), formula (IV), One of particular compound of formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) compound or the embodiment of the present application or its Pharmaceutically acceptable salt, solvate and/or ester.

Present invention also provides formula (I) compound or its pharmaceutically acceptable salt, solvate and/or ester, which is used for The pneumonitis viruss subfamily virus infection for the treatment of people or respiratory syncytial virus infection.

Single embodiment is additionally provided, which includes formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), one of particular compound of formula (VIII), formula (IX) compound or the embodiment of the present application or which is pharmaceutically acceptable Salt, solvate and/or ester, which is used for the infection of pneumonitis viruss subfamily virus or the respiratory syncytial virus infection for treating people.

Present invention also provides compound as described in this description.Present invention also provides as described in this description Pharmaceutical composition.Present invention also provides the method for using formula (I) compound, as described in this description.The application is also carried The method for having supplied to prepare formula (I) compound, as described in this description.

The metabolite of compound

The interior metabolism product of herein described compound is also fallen in scope of the present application, and the product is relative to existing skill It is novel for art and is non-obvious.The product may result from the oxidation of compound for example be administered, reduction, water Solution, amidatioon, esterification etc., mainly due to enzymolysis process.Therefore, by including making compound be enough to produce with mammalian animal Novel and non-obvious compound produced by the process of the time of raw its metabolite is included in the invention.It is such Product is identified typically by following：Prepare radioactive label (such as 14C or 3H) compound, with detectable dosage (example Such as larger than about 0.5mg/kg) to animal (such as rat, mice, Cavia porcelluss, monkey or people) parenteral, permission time enough Carry out metabolism (normally about 30 seconds to 30 hours) and its converted product is separated from urine, blood or other biological sample.These products Thing is easily isolated, because they are that labeled (other are come using the antibody for being capable of epi-position present in conjugated metabolite Separate).The metabolite structure is determined in a usual manner, for example, is analyzed by MS or NMR.Generally, the analysis of metabolite To carry out with conventional drug metabolism well known to those skilled in the art research identical mode.As long as converted product they not with which His mode is occurred in vivo, you can for the diagnostic test of the therapeutic dose of compound, even if they do not have their own HSV antiviral activities.

The formula and method for determining stability of the compound in the gastrointestinal secretion thing for substituting is known.When in 37 DEG C of guarantors , after 1 hour, when less than about the protected group of 50 moles of % is deprotected in the intestinal juice or gastric juice for substituting, compound is in this Shen for temperature Please be defined as gastrointestinal tract stable.Merely because to gastrointestinal tract, compound is stably not meant to that they will not hydrolyze in vivo.Before Medicine generally will be stablized in digestive system, but may be generally in gastrovascular cavity, liver, lung or other metabolic organs or big in the cell Amount is hydrolyzed to parent drug.As used in this application, prodrug is interpreted as Jing chemical design to overcome the biological barrier of oral delivery The compound of parent drug is discharged afterwards effectively.

Useful oxygen protection group includes first silicon substrate ether protection group or benzyl-type protecting group, including methoxy-benzyl.

Useful first silicon substrate ether protection group includes trimethyl silicon substrate (TMS), triethyl group silicon substrate (TES), dimethylisopropyl Silicon substrate (IPDMS), diethyl isopropyl silicon substrate (DEIPS), dimethylhexanyl silicon substrate (TDS), t-Butyldimethylsilyl (TBS Or TBDMS), tert-butyl diphenyl silicon substrate (TBDPS), tri-benzyl-silyl, three xylol base silicyl (Tri-p- Xylylxilyl), triisopropylsilyl (TIPS), diphenyl methyl silicon substrate (DPMS), di-t-butyl methylsilyl (DTBMS), Triphenyl silicon substrate (TPS), methyldiphenyl base silicon substrate (MDPS), tert-butyl group methoxyphenyl silicon substrate, three (trimethyl silicon substrate) silicon substrate (sisyl), (2- hydroxy styrenes bases) dimethyl silicon substrate (HSDMS), (2- hydroxy styrenes bases) diisopropyl silicon substrate (HSDIS), tert-butyl group methoxyphenyl silicon substrate (TBMPS) and tert-butoxy diphenyl silicon substrate (DPTBOS) protection group.

Useful benzyl-type protecting group includes benzyl, halogeno-benzyl, to methoxy-benzyl, benzyloxymetliyl, 2,4- bis- Methoxy-benzyl, 3,4- dimethoxy-benzyls, 2,6- dimethoxy-benzyls, p- CF₃- benzyl, p- methyl-benzyl, p- methoxy Base benzyl, 3,5- dimethyl benzyls, p- t-butylbenzyl, o- nitrobenzyl, p- nitrobenzyl, p- halogeno-benzyl (include P- bromobenzyl), 2,6- dichloro benzyls, p- cyanobenzyls, p- phenylbenzyl, 2,6- difluorobenzyls, p- acyl amino benzyl (PAB), p- azido benzyl (Azb), 4- azido -3- chlorobenzyls, 2- trifluoromethyl benzyls, p- (methylsulfinyl) benzyl Base, 2- picolyls, 4- picolyls, 3- methyl -2- picolyl N-oxides, 2- quinolyl methyls, diphenyl methyl (DPM), p, p '-dinitro benzhydryl, trityl group, Alpha-Naphthyl diphenyl methyl, p- methyoxyphenyldiphenylmethyl Base, two (p- methoxyphenyl) phenyl methyl, three (p- methoxyphenyl) methyl, 4,4 ', 4 "-three (benzoyloxyphenyls) Methyl and 2- naphthyl methyl protection groups.

Useful amine protecting group includes p- methoxy-benzyl carbonyl (Moz or MeOZ), acetyl group (Ac), benzoyl (Bz), p- methoxy-benzyl (PMB), 3,4- dimethoxy-benzyls (DMPM), p- methoxyphenyl (PMP), tosyl (Ts or Tos), trifluoroacetamide and trityl-protecting group.

Useful amine protecting group also includes carbamate and amide protecting group.The example of carbamate protective group includes Methyl carbamate and urethanes, such as 9- fluorenylmethyloxycarbonyls (FMOC), 9- (2- are formed with amine to be protected Sulfo group) fluorenyl methyl, 9- (2,7- dibromos) fluorenyl methyl, 17- tetra- benzos [a, c, g, i] fluorenyl methyls (Tbfmoc), the chloro- 3- of 2- Indenyl methyl (Climoc), benzo [f] indenes -3- ylmethyls (Bimoc), 2,7- di-t-butyls [9- (10,10- dioxo -10, 10,10,10- tetra- Qing thioxane bases (thioxanyl))] methyl (DBD-Tmoc), [2- (1,3- dithiane bases) methyl (Dmoc) With the carbamate of 1,1- dioxo benzo [b] thiophene -2- ylmethyls (Bsmoc).

The example of useful substituted urethanes includes 1,1- dimethyl -2- cyano ethyls, 2- phosphorio ethyls (Peoc), 2- methylsulfanylethyls, 2- (ptoluene-sulfonyl) ethyl, 2,2,2 ,-trichloroethyl (Troc), 2- (trimethyl silicanes Base) ethyl (Teoc), 2- phenylethyls (hZ), 1- (1- adamantyls) -1- Methylethyls (Adpoc), 1,1- dimethyl -2- bromines Ethyl, 1,1- dimethyl -2- chloroethyls, 1,1- dimethyl -2,2- dibromoethyls (DB-t-BOC), 1,1- dimethyl -2,2,2- Trichloroethyl (TCBOC), 1- methyl isophthalic acids-(4- xenyls) ethyl (Bpoc), 1- (3,5- di-t-butyl phenyl) -1- methyl second Double (4 '-nitrobenzophenone) ethyls of base (t-Bumeoc), 2- (2 ' pyridine radicals) ethyl, 2- (4 ' pyridine radicals) ethyl, 2,2- (Bnpeoc), N- (2- pivaloyl group amino) -1,1- dimethyl ethyls, 2- [(2- nitrobenzophenones) disulfide group] -1- phenylethyls (NpSSPeoc), 2- (N, N- dicyclohexyl formamido) ethyl, the tert-butyl group (Boc or BOC), 1- adamantyls (1-Adoc), 2- adamantyls (2-Adoc), vinyl (Voc), pi-allyl (Aloc or alloc), 1- isopropylallyls (Ipaoc), Cortex Cinnamomi Base (Coc), 4- nitrocinnamyl bases (Noc), 3- (3 '-pyridine radicals) propyl- 2- thiazolinyl (Paloc), 8- quinolyls and N- hydroxy piperidines The carbamate and aminodithioformic acid Arrcostab of base, including aminodithioformic acid methyl ester, aminodithioformic acid Ethyl ester, aminodithioformic acid isopropyl ester, the aminodithioformic acid tert-butyl ester and aminodithioformic acid phenyl ester.

Also usefully contain aryl and the carbamate containing the aryl for replacing, for example benzyl, p- methoxy-benzyl, p- Nitrobenzyl, p- bromobenzyl, p- chlorobenzyl, 2,4- dichloro benzyls, 4- methylsulfinyl benzyls (Msz), 9- anthrylmethyls, 4- methylthiophene bases (Mtpc), 1- methyl isophthalic acids-(triphenyl phosphorio) ethyl (2- triphenylphosphonioisopropyls) (Ppoc), 2- it is red Methylaminosulfonylethyl (Dnseoc), 2- (4- nitrobenzophenones) ethyl (Npeoc), 4- phenylacetyl oxy-benzyls (PhAcOZ), 4- nitrine Base benzyl (ACBZ), 4- azido methoxy-benzyls, m- chloro- p- acyloxybenzyl, p- (dihydroxy boryl) benzyl, benzyloxy Carbonyl (Cbz), 4- benzoisoxazole ylmethyls (Bic), 2- (trifluoromethyl) -6- chromone ylmethyls (Tcroc), phenyl and hexichol The carbamate of ylmethyl.Extra carbamate includes butynyl, cyclopenta, cyclohexyl, Cvclopropvlmethvl, 1- methyl The carbamate of cyclobutyl, 1- methylcyclohexyls, 1,1- alkynyl dimethyls and 1- methyl isophthalic acids-Cvclopropvlmethvl.

The useful amide protecting group of amine includes N- formoxyls, N- acetyl group, N- chloracetyls, N- tribromo-acetyl bases, N- Trifluoroacetyl group (TFA), N- phenyl acetyls, N-3- PHENYLPROPIONYLs, N-4- pentenoyls, N-2- picolinoyls, N-3- The amide of pyridylcarboxamide amido, N- benzoylphenylalanyl bases, N- benzoyls and the p- Phenylbenzoyls of N-.

The list that table 1. is abridged with acronym.

Net reaction

Reaction equation 1 shows the general synthesis of the compounds of this invention, and which is from suitable core base S1b (X¹=halogen ,- O- alkyl ,-O- aryl ,-S- alkyl ,-S- aryl, NH₂、NHR^a、NR^a ₂；X²=Br, I) lithium-halogen exchange (such as n-BuLi) Reaction starting, then with lactone S1a additions.In Lewis acid (such as BF₃·Et₂O, Et₃SiH the side base 1 ' is reduced under the conditions of) Hydroxyl produces intermediate S1c.The standard of hydroxyl protecting group changes the intermediate S1d for providing suitably protecting.Then by the 5 ' hydroxyls of S1d Base changes into corresponding iodide (such as I₂, PPh₃), then processed to carry out eliminating anti-with alkalescence condition (such as DBU) Should be so as to producing intermediate S1e.The oxidation of alkene S1e and addition (such as ICl, the NaN of azido compound₃) there is provided intermediate S1f.S1g is produced and by X with oxygen nucleophiles (such as MCPBA, MCBA) displacement iodide S1f¹Group changes into-NH₂(for example NH₄OH), obtain the final compound of S1h types.

Reaction equation 2 shows the general synthesis of intermediate of the present invention, its under oxidizing condition (such as EDCI) by 5 ' hydroxyls It is initial that base S1d changes into aldehyde S2a.Corresponding enolate is condensed into (such as CH with formaldehyde₂O, NaOH) and reduce (for example NaBH₄) obtain intermediate S2b.Intermediate S2c is obtained with the continuous selective protection hydroxylic moiety of orthogonal protection group.In oxidation bar Hydroxyl S2c is changed into into aldehyde under part (such as EDCI) and obtains intermediate S2d.The preparation of aldehyde S2d to nitrile S2e can be formed by oxime (such as NH₂OH) and oxime alcohol elimination (such as CDI) realizing.By X¹Group changes into-NH₂(such as NH₄OH S2f classes) are obtained The final compound of type.

Reaction equation 3 is shown by the preparation of alcohol S2c come general synthesis intermediate of the present invention.The deoxidation of alcohol S2c is (for example PPh₃、I₂, then Bu₃SnH, AIBN) and X¹Group is to-NH₂Conversion (such as NH₄OH) obtain the final compound of S3a types. Methylate (such as MeI) and the X of alcohol S2c¹Group is to-NH₂Conversion (such as NH₄OH) obtain the final compound of S3b types. Chlorination (such as POCl of alcohol S2c₃) and X¹Group is to-NH₂Conversion (such as NH₄OH) obtain the final compound of S3c types. The fluorination (such as DAST) of alcohol S2c and X¹Group is to-NH₂Conversion (such as NH₄OH) obtain the final compound of S3d types.

Reaction equation 4 is shown by preparing aldehyde S2d come general synthesis intermediate of the present invention.The alkylene of aldehyde S2d is (for example Ph₃PCH₂) and X¹Group is to-NH₂Conversion (such as NH₄OH) obtain the final compound of S4a types.The reduction of alkene is (for example H₂, Pd/C) and obtain the final compound of S4b types.The bifluoride (such as DAST) of aldehyde S2d and X¹Group is to-NH₂Conversion (example Such as NH₄OH) obtain the final compound of S4c types.Cyclopropanated (such as CH of alkene S4a₂N₂) and X¹Group is to-NH₂Turn Change (such as NH₄OH) obtain the final compound of S4d types.

Reaction equation 5 show by prepare triflate S5a (according to WO2013138236A1, It is prepared by WO2012037038A1, WO2012012776A1) carry out general synthesis intermediate of the present invention.Triflate S5a is used The replacement of fluorine nucleopilic reagent (such as CsF), hydrolysis (such as TFA, the H of methoxyl group acetal₂O) and oxidation (such as PDC) obtain S5b The compound of type, which is suitable to be coupled with core base.The replacement of chlorine nucleopilic reagent (such as LiCl) of triflate S5a, Hydrolysis (such as TFA, the H of methoxyl group acetal₂O) and oxidation (such as PDC) obtains the compound of S5c types, which is suitable to and core alkali Base is coupled.Triflate S5a nitrine nucleopilic reagent (such as NaN₃) replacement, methoxyl group acetal hydrolysis (for example TFA, H₂O) and oxidation (such as PDC) obtains the compound of S5d types, which is suitable to and core base is coupled.Triflate S5a With the replacement of cyanide nucleopilic reagent (such as NaCN), hydrolysis (such as TFA, the H of methoxyl group acetal₂O) and oxidation (such as PDC) The compound of S5e types is obtained, which is suitable to be coupled with core base.

Reaction equation 6 is shown by preparing alkali S6a (preparing according to WO2008073785A2) come the general synthesis present invention Intermediate.Amination (such as NH of S6a alkali₃) S6b is obtained, which is acylated (such as Ac₂O) producing S6c.Add nucleophilic fluorine (for example CsF) obtain S6d and remove acyl group (such as NH₃) final compound of S6e types is obtained, which is adapted for coupling to lactone.

Reaction equation 7 shows the general synthesis of the compounds of this invention, and which includes that the phosphorylation for synthesizing S7b types is similar to Thing.

Reaction equation 8 shows the general synthesis of the compounds of this invention, and which includes that the phosphorylation for synthesizing S7b types is similar to Thing.

Reaction equation 9 shows the general synthesis of the compounds of this invention, and which includes that the phosphorylation for synthesizing S9c types is similar to Thing.

Experiment

Bromo- 4- phenoxy groups thieno [3,2-d] pyrimidines of intermediate 1b-7-.

By 7- bromo- 4- chlorothiophenes simultaneously [3,2-d] pyrimidine (1a, purchased from Pharmablock Inc., 5.00g, 20.0mmol), Phenol (1.90g, 20.2mmol) and Cs₂CO₃The mixture of (7.8g, 24.0mmol) in MeCN (50mL) is stirred at 40 DEG C 16h.The reactant mixture is quenched with AcOH (1.8mL) and concentrating under reduced pressure.By residue H₂O (25mL) process is then by institute Solid must be separated out by collected by suction.By solid H₂O is washed, then with hexane-ethylacetate (4:1) wash and be dried, (6.16g, 88%), which is white solid to obtain intermediate 1b.

¹H NMR (400MHz, CDCl₃) δ 8.85 (s, 1H), 7.97 (s, 1H), 7.51-7.45 (m, 2H), 7.36-7.30 (m, 1H), 7.27-7.25 (m, 2H).MS m/z=307.1,309.1 [M+1]

Intermediate 1d- (3R, 4R, 5R) -4- (benzyl epoxide) -5- ((benzyl epoxide) methyl) -3- fluoro- 2- (4- phenoxy groups Thieno [3,2-d] pyrimidin-7-yl) tetrahydrofuran -2- alcohol

At -78 DEG C, to bromo- 4- phenoxy groups thieno [3, the 2-d] pyrimidines (1b, 5.1g, 16.6mmol) of 7- and (3R, 4R, 5R) -4- (benzyl epoxide) -5- ((benzyl epoxide) methyl) -3- fluorine dihydrofuran -2 (3H) -one (1c, WO2012012776A1, 5.5g, 16.6mmol) Deca nBuLi (hexane solution of 2.5M, 8.0mL, 20mmol) is held in solution in THF (300mL) Continuous 30min.The reactant mixture is stirred into 30min at -78 DEG C and is quenched with AcOH (1.5mL).Gained mixture is warmed to Room temperature.The reactant mixture ethyl acetate (300mL) is diluted and washed with water.By organic faciess anhydrous Na₂SO₄It is dried simultaneously Concentrating under reduced pressure.By residue over silica gel column chromatography purification, with hexane-ethylacetate (6:1-3:1) eluting, obtains isomer mixing (5.5g, 59%), which is faint yellow oil to thing 1d.

MS m/z=558.9 [M+1].

Intermediate 1e-7- ((2S, 3S, 4R, 5R) -4- (benzyl epoxide) -5- ((benzyl epoxide) methyl) -3- fluorine tetrahydrochysene furans Mutter -2- bases) -4- phenoxy group thieno [3,2-d] pyrimidines

In room temperature, to intermediate 1d (5.5g, 10mmol) in CH₂Cl₂(50mL) Et is added in the solution in₃SiH (4.6g, 39mmol), it is subsequently adding BF₃·Et₂O (4.2g, 30mmol).The mixture is stirred at room temperature into 7 days.By the reactant mixture Cooled down with ice-water bath and use NaHCO₃(20g) in H₂Solution in O (100ml) is slowly quenched.Organic faciess are separated, Na is used₂SO₄It is dry It is dry and use silica gel chromatography, with hexane-ethylacetate (6:1-4:1) eluting, obtain intermediate 1e (3g, 56%).

¹H NMR (400MHz, CDCl₃) δ 8.73 (s, 1H), 8.15 (s, 1H), 7.5-7.45 (m, 2H), 7.4-7.2 (m, 13H), 5.71 (d, J=24.8Hz, 1H), 5.28 (dd, J=55,3.6Hz, 1H), 4.75-4.45 (m, 4H), 4.38-4.25 (m, 2H), 3.98 (dd, J=10.8,2Hz, 1H), 3.72 (dd, J=10.8,2Hz, 1H).¹⁹F NMR (376MHz, CDCl3) δ- 195.25 to -195.51 (m).MS m/z=543.1 [M+1].

Intermediate 1f-7- ((2S, 3S, 4R, 5R) -4- (benzyl epoxide) -5- ((benzyl epoxide) methyl) -3- fluorine tetrahydrochysene furans Mutter -2- bases) thieno [3,2-d] pyrimidine -4- amine

By intermediate 1e (3g, 5.53mmol), NH₄The mixture of OH (28%, 50mL) and MeCN (50mL) is at 65 DEG C 64h is stirred in sealed flask.HPLC analyses show about 40% conversion.It is subsequently adding extra NH₄OH (28%, 50mL) and MeCN(50mL).The reactant mixture is stirred for into 36h at 70 DEG C.HPLC analyses show about 75% conversion.Then it is this is anti- Answer mixture to concentrate and use silica gel chromatography, with ethyl acetate (25-100%)-Hex, obtain intermediate 1f (1.3g).The initiation material (intermediate 1e, 0.82g) of residual is reclaimed and at 70 DEG C with NH₄The 2Me- of OH (28%, 50mL) THF (25mL) solution and EtOH (25mL) reprocessing.After 64h, by gained mixture concentrating under reduced pressure and silica column purification is used, use second Acetoacetic ester (25-100%)-Hex, obtains extra 0.75g intermediate 1f.2.05g (80%) intermediate is obtained always 1f。

¹H NMR (400MHz, CDCl₃) δ 8.51 (s, 1H), 7.99 (d, J=1.2Hz, 1H), 7.38-7.25 (m, 10H), 5.75 (wide s, 2H), 5.65 (d, J=24.8Hz, 1H), 5.25 (dd, J=55,3.6Hz, 1H), 4.75-4.45 (m, 4H), 4.38-4.2 (m, 2H), 3.98 (dd, J=10.8,2Hz, 1H), 3.72 (dd, J=10.8,2Hz, 1H).¹⁹F NMR (376MHz, CDCl₃) δ -195.12 to -195.39 (m).MS m/z=466.1 [M+1].

Intermediate 1g-N- (7- ((2S, 3S, 4R, 5R) -4- (benzyl epoxide) -5- ((benzyl epoxide) methyl) -3- fluorine tetrahydrochysenes Furan -2- bases) thieno [3,2-d] pyrimidine-4-yl) Benzoylamide

At 0 DEG C, Benzenecarbonyl chloride. is added in solution of the intermediate 1f (2.05g, 4.4mmol) in pyridine (15mL) (1.86g, 13.2mmol).The reactant mixture is stirred at room temperature into 1h.The reactant mixture ice-water bath is cooled down and is used in combination MeOH (5mL) is quenched.Gained reactant mixture is stirred into 16h at 45 DEG C.HPLC and LC-MS show the 6-NBz₂Change into 6- NHBz.By the reactant mixture concentrating under reduced pressure.By residue with ethyl acetate and water process.Organic faciess are separated, Na is used₂SO₄It is dried And use silica gel chromatography, with ethyl acetate (20-50%)/Hex, obtain intermediate 1g (2.1g, 85%).

¹H NMR (400MHz, CDCl₃) δ 8.81 (s, 1H), 8.24 (s, 1H), 8.06 (d, J=7.2Hz, 2H), 7.66 (t, J=7.2Hz, 1H), 7.56 (apparent-t, J=7.6Hz, 2H), 7.37-7.25 (m, 10H), 5.73 (d, J=24.8Hz, 1H), 5.22 (dd, J=54.8,3.6Hz, 1H), 4.71-4.45 (m, 4H), 4.4-4.20 (m, 2H), 3.98 (dd, J=10.8, 2Hz, 1H), 3.72 (dd, J=10.8,3.2Hz, 1H).¹⁹F NMR (376MHz, CDCl₃) δ -189.77 to -190.04 (m).MS M/z=570.1 [M+1].

Intermediate 1h-N- (7- (fluoro- 4- hydroxyls -5- (hydroxymethyl) tetrahydrofuran -2- bases of (2S, 3R, 4R, 5R) -3-) thiophenes Fen simultaneously [3,2-d] pyrimidine-4-yl) Benzoylamide

By the intermediate 1g (2.1g, 3.69mmol) and toluene (2 × 6mL) coevaporation.Residue is dissolved in into acetic acid second Methanesulfonic acid (4mL) is added in ester (2mL) and at 0 DEG C.After 3h, extra methanesulfonic acid (1mL) is added.By the reactant mixture in room Temperature is stirred for 4h, the reactant mixture is diluted with ethyl acetate (50mL) afterwards.Gained mixture is cooled to into 0 DEG C and divides 4 Criticize and add solid NaHCO₃(12.0g).Gained mixture is stirred into 1h at 0 DEG C, 16h is then stirred at room temperature.It is mixed to the reaction Water (25mL) is slowly added in compound.The mixture is stirred into 0.5h, then filters to remove remaining solid.Organic faciess saline Washing, uses Na₂SO₄It is dried and concentrating under reduced pressure.By residue over silica gel column purification, with methanol (0-10%)/dichloromethane eluent, Obtain intermediate 1h (0.79g, 55%).

¹H NMR (400MHz, CD₃OD) δ 8.87 (s, 1H), 8.37 (d, J=0.8Hz, 1H), 8.05 (d, J=7.2Hz, 2H), 7.66 (t, J=7.6Hz, 1H), 7.56 (apparent-t, J=7.6Hz, 2H), 5.57 (apparent dd, J=24,1.6Hz, 1H), 5.12 (ddd, J=54.8,4,1.6Hz, 1H), 4.31 (ddd, J=19.6,8,4Hz, 1H), 4.07-4.02 (m, 1H), 4.0 (dd, J=12.4,2.4Hz, 1H), 3.79 (dd, J=12.4,4Hz, 1H).¹⁹F NMR (376MHz, CD₃OD)δ-202.76 To -203.03 (m).MS m/z=390.1 [M+1].

Intermediate 1i-N- (7- (fluoro- 4- hydroxyls -5- (iodo-methyl) tetrahydrofuran -2- bases of (2S, 3R, 4R, 5S) -3-) thiophenes Fen simultaneously [3,2-d] pyrimidine-4-yl) Benzoylamide

In room temperature, to intermediate 1h (0.79g, 2.03mmol), Ph₃P (1.20g, 4.58mmol) and imidazoles (0.277g, Iodine (0.96g, 3.78mmol) is added in the solution in THF (15mL) 4.07mmol).After 4h, by NaHCO₃(solid, 500mg) add in the reactant mixture, water (200 μ L) is subsequently adding so that the reaction is quenched.The reactant mixture is concentrated and incited somebody to action Residue over silica gel column purification, with ethylacetate-hexane (1:1) eluting, (0.85g, 84%), which is solid to obtain intermediate 1i Body.

¹H NMR (400MHz, CDCl₃) δ 9.05 (wide s, 1H), 8.84 (s, 1H), 8.29 (d, J=1.2Hz, 1H), 8.03 (d, J=7.6Hz, 2H), 7.68-7.63 (m, 1H), 7.56 (apparent-t, J=7.6Hz, 2H), 5.67 (apparent d, J= 27.2Hz, 1H), 5.27 (ddd, J=55.2,4.4,0.8Hz, 1H), 4.17 (ddd, J=20.8,8.4,4.4Hz, 1H), 3.79-3.75 (m, 1H), 3.72 (dd, J=10.8,3.6Hz, 1H), 3.53 (dd, J=10.8,4.8Hz, 1H).¹⁹F NMR 376MHz, CDCl₃) δ -193.33 to -193.61 (m).MS m/z=500.0 [M+1].

Intermediate 1j-N- (7- (the fluoro- 4- hydroxyls -5- methylene tetrahydrofuran -2- bases of (2S, 3R, 4R) -3-) thieno [3, 2-d] pyrimidine-4-yl) Benzoylamide

To in solution of the intermediate 1i (0.84g, 1.68mmol) in THF (5mL) add DBU (0.68g, 4.47mmol).The reactant mixture is stirred at room temperature into 16h and is then heated to 45 DEG C.After 8h, the reactant mixture is cooled to Room temperature by the reactant mixture concentrating under reduced pressure.Residue is dissolved in into CH₂Cl₂In and load to silicagel column, use ethyl acetate (50-100%)-Hex, (0.45g, 72%), which is solid to obtain intermediate 1j.

¹H NMR (400MHz, DMSO-d₆) δ 11.65 (wide s, 1H), 8.98 (s, 1H), 8.22 (d, J=1.2Hz, 1H), (8.08 d, J=7.6Hz, 2H), 7.66 (t, J=7.6Hz, 1H), 7.55 (t, J=7.6Hz, 2H), 5.82 (d, J=21.6Hz, 1H), 5.81 (d, J=8Hz, 1H), 5.24 (dd, J=54.4,4Hz, 1H), 4.85-4.72 (m, 1H), 4.43 (wide s, 1H), 4.17 (t, J=1.6Hz, 1H).¹⁹F NMR (376MHz, DMSO-d₆) δ -201.19 to -201.46 (m).MS m/z=371.9 [M+1]。

Intermediate 1k-N- (7- (fluoro- 4- hydroxyls -5- (iodo-methyl) tetrahydrofurans of (2S, 3R, 4R) -5- azido -3- - 2- yls) thieno [3,2-d] pyrimidine-4-yl) Benzoylamide

At 0 DEG C (ice-water bath), to NaN₃ICl is added in the suspension of (400mg, 6.15mmol) in DMF (10mL) (400mg, 2.46mmol).Gained mixture is stirred into 10min at 0 DEG C and lasting 20min is warmed to room temperature.The reaction is mixed Thing ice-acetone bath cools down and adds DMF (2mL) solution of intermediate 1j (400mg, 1.08mmol).Gained reaction is mixed Thing stirs 1h at 0 DEG C, afterwards by reaction Na₂S₂O₃Aqueous solution (1M, 3mL) is quenched.By the reactant mixture concentrating under reduced pressure simultaneously With CH₃CN coevaporations.By residue CH₂Cl₂Process and filter.Filtrate is loaded to silicagel column, hexane-ethylacetate is used (1:1) eluting, (410mg, 70%), which is solid to obtain intermediate 1k.NMR analyses show that it is the 45 of 4 '-position:55 end groups Heterogeneous mixture.

¹H NMR (400MHz, DMSO-d₆) δ 11.64 (wide s, 1H), 8.98 (s, 1H), 8.56 (s, 0.45H), 8.43 (s, 0.55H), 8.08 (d, J=8Hz, 2H), 7.66 (t, J=8Hz, 1H), 7.55 (t, J=8Hz, 2H), 6.47 (d, J=6Hz, 0.45H), 6.26 (d, J=7.2Hz, 0.55H), 5.9-5.25 (m, 2H), 4.75-4.45 (m, 1H), 3.74 (s, 1H), 3.62- 3.52 (m, 1H).¹⁹F NMR (376MHz, DMSO-d₆) δ -197.24 to -197.51 (m) (main isomer), -208.52 to - 208.73 (m) (secondary isomer).MS m/z=540.9 [M+1].

Intermediate 1l-3- chlorobenzoic acids ((2R, 3R, 4R, 5S) -2- azido -5- (4- benzamido thieno [3,2- D] pyrimidin-7-yl) the fluoro- 3- hydroxyl tetrahydrofurans -2- bases of -4-) methyl ester

To intermediate 1k (400mg, 0.74mmol), 3- chlorobenzoic acids (300mg, 1.92mmol), 4-butyl ammonium hydrogen sulfate (275mg, 0.81mmol) and dipotassium hydrogen phosphate (3H₂O, 830mg, 3.64mmol) in CH₂Cl₂(50mL) and H₂In O (10mL) Solution in add metachloroperbenzoic acid (77%, 750mg, 3.35mmol).Gained reactant mixture is stirred at room temperature into 4h. The reactant mixture ice-water bath is cooled down and uses Na₂S₂O₃Aqueous solution (1M, 5mL) is extracted.By gained mixture concentrating under reduced pressure simultaneously Residue is dissolved in ethyl acetate.By organic faciess saturation NaHCO₃Solution washing, with anhydrous sodium sulfate drying and reduces pressure Concentration.By residue over silica gel column purification, with hexane/ethyl acetate (2:1) eluting, obtains two kinds of isomers：Elute first Required isomer intermediate 1l (135mg, 32%, obtain soon than isomer B eluting on silica gel and C-18HPLC) and second Eluting is unwanted isomer (70mg, 17%, slow than isomer A on silica gel and C-18HPLC).

Isomer 1l needed for eluting first：¹H NMR (400MHz, CDCl₃) δ 8.95 (wide s, 1H), 8.74 (wide s, 1H), 8.08 (s, 1H), 8.02 (d, J=8Hz, 2H), 7.97 (t, J=1.6Hz, 1H), 7.91-7.87 (m, 1H), 7.66 (t, J =8Hz, 1H), 7.59-7.52 (m, 3H), 7.38 (t, J=8Hz, 1H), 5.80 (d, J=26.8Hz, 1H), 5.40 (dd, J= 54.8,4.8Hz, 1H), 4.89 (dd, J=21.6,5.2Hz, 1H), 4.80 (d, J=12Hz, 1H), 4.67 (d, J=12Hz, 1H)。¹⁹F NMR (400MHz, CDCl₃) δ -192.61 to -192.88 (m).MS m/z=569.0 [M+1].

Second elutes unwanted isomer：¹H NMR (400MHz, CDCl₃) δ 9.1 (wide s, 1H), 8.87 (wide s, 1H), 8.16 (s, 1H), 8.08-7.98 (m, 4H), 7.66 (t, J=7.6Hz, 1H), 7.59-7.55 (m, 3H), 7.41 (t, J= 7.6Hz, 1H), 5.86 (dd, J=18.4,4.4Hz, 1H), 5.74 (ddd, J=53.2,4.8,4.8Hz, 1H), 4.83 (d, J= 12Hz, 1H), 4.78 (d, J=12Hz, 1H), 4.48 (dd, J=10,4.8Hz, 1H).¹⁹F NMR (400MHz, CDCl₃)δ- 205.15 to -205.53 (m).MS m/z=568.9 [M+1].

Embodiment 1- (2R, 3R, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) -2- azido -4- are fluoro- 2- (hydroxymethyl)-tetrahydrofuran -3- alcohol

By intermediate 1l (135mg, 0.237mmol) and NH₄Solution of the OH (28%, 3mL) in MeOH (3mL) is at 45 DEG C Stirring 16h.By the reactant mixture concentrating under reduced pressure.By residue by preparative-HPLC purification, obtain embodiment 1 (54mg, 70%).

¹H NMR (400MHz, DMSO-d₆) δ 8.40 (s, 1H), 8.24 (s, 1H), 7.67 (wide s, 2H), 5.85 (wide s, 1H), 5.62 (d, J=23.6Hz, 1H), 5.14 (ddd, J=55.2,4.8,2Hz, 1H), 4.46 (dd, J=24.0,4.8Hz, 1H), 3.70 (d, J=12Hz, 1H), 3.56 (d, J=12Hz, 1H).¹⁹F NMR (376MHz, DMSO-d₆) δ -197.67 to - 197.94(m).MS m/z=327.0 [M+1].

Intermediate 2a-N- (7- ((2S, 3R, 4R, 5R) -5- ((double (4- methoxyphenyls) (phenyl) methoxyl groups) methyl) - The fluoro- 4- hydroxyl tetrahydrofurans -2- bases of 3-) thieno [3,2-d] pyrimidine-4-yl) Benzoylamide

In room temperature, disposably add in solution of the intermediate 1h (2.0g, 5.14mmol) in pyridine (20mL) DMTrCl (2.52g, 7.45mmol).Gained mixture is stirred at room temperature into 40min, methanol (5mL) is added afterwards.This is mixed Thing is concentrated in vacuo and with silica gel column chromatography (0-70% ethyl acetate is in hexane) purification, obtain intermediate 2a (2.5g, 70%), Which is white foam.MS m/z=692 [M+1]

Intermediate 2b-N- (7- ((2S, 3S, 4R, 5R) -5- ((double (4- methoxyphenyls) (phenyl) methoxyl groups) methyl) - 4- ((t-Butyldimethylsilyl) epoxide) -3- fluorine tetrahydrofuran -2- bases) thieno [3,2-d] pyrimidine-4-yl) Benzoylamide

In room temperature, in solution of the intermediate 2a (2.5g, 3.61mmol) in DMF (20mL) add imidazoles (738mg, 10.8mmol) with TBSCl (817mg, 5.42mmol).The mixture is stirred into 7h and MeOH (5mL) is added.After 5min stirrings, The mixture is diluted with EtOAc and washed with water and sodium bicarbonate solution.Organic layer is dried with sodium sulfate and concentrated in vacuo.Will Residue over silica gel column chromatography purification (hexane solution of 0-70% ethyl acetate), obtains intermediate 2b (3.0g, 86%, 84% Purity), which is white solid.MS m/z=806 [M+1]

Intermediate 2c-N- (7- ((2S, 3S, 4R, 5R) -4- ((t-Butyldimethylsilyl) epoxide) fluoro- 5- (hydroxyls of -3- Methyl) tetrahydrofuran -2- bases) thieno [3,2-d] pyrimidine-4-yl) Benzoylamide

In room temperature, the Deca in solution of the intermediate 2b (3.0g, 3.7mmol) in DCM (20mL) and MeOH (10mL) TFA (1.50mL, 19.6mmol).The mixture is stirred into 1h, is used sodium bicarbonate solution (5mL) to process and use dichloro afterwards Methane dilutes.Washed with sodium bicarbonate solution by the phase separation and by organic faciess, be dried with sodium sulfate and concentrating under reduced pressure.By remnants With silica gel chromatography (hexane solution of 0-90% ethyl acetate), (1.6g, 85%), which is white to thing to obtain intermediate 2c Solid.MS m/z=504 [M+1]

Intermediate 2d-N- (7- ((2S, 3S, 4R, 5S) -4- ((t-Butyldimethylsilyl) epoxide) the fluoro- 5- formoxyls of -3- Tetrahydrofuran -2- bases) thieno [3,2-d] pyrimidine-4-yl) Benzoylamide

To intermediate 2c (1.6g, 3.18mmol) in DMSO- toluene (10:1- ethyl -3- are added in solution in 5mL) (3- dimethylaminopropyls) carbodiimide HCl (1.83g, 9.53mmol), pyridine (0.26mL, 3.12mmol) and TFA (0.15mL, 1.91mL).Gained mixture is stirred at room temperature into 2h and methanol (5mL) is added.By gained mixture dichloromethane Alkane dilutes, and with water and salt water washing, is dried with sodium sulfate and concentrated in vacuo, obtains crude intermediate 2d (1.4g), and which is direct For next reaction.

Intermediate 2e-N- (7- ((2S, 3S, 4R, 5S) -4- ((t-Butyldimethylsilyl) epoxide) the fluoro- 5- formyls of -3- Base -5- (hydroxymethyl) tetrahydrofuran -2- bases) thieno [3,2-d] pyrimidine-4-yl) Benzoylamide

By crude intermediate 2d (1.4g, 2.79mmol) be dissolved in THF (20mL) and add 37%wt formaldehyde (1.70mL, 22.8mmol) with 2N NaOH aqueous solutions (2.80mL, 5.58mmol).Gained mixture is stirred at room temperature into 2h.It is subsequently adding volume Outer formaldehyde (2mL) and 2N NaOH aqueous solutions (2mL).After 30min, the mixture is neutralized with AcOH, diluted with EtOAc, used Sodium bicarbonate solution and salt water washing, are dried with sodium sulfate and concentrated in vacuo, obtain intermediate 2e (1.4g), and which is yellow bubble Foam, is directly used in next step.

Intermediate 2f-N- (7- (double (the hydroxyls of the fluoro- 5,5- of (2S, 3S, 4R) -4- ((t-Butyldimethylsilyl) epoxide) -3- Methyl) tetrahydrofuran -2- bases) thieno [3,2-d] pyrimidine-4-yl) Benzoylamide

Then intermediate 2e (1.4g, 2.63mmol) is dissolved in ethanol (15mL) and sodium borohydride is dividedly in some parts at 0 DEG C (110mg, 2.90mmol) continues 5min.After 15min is stirred in ice-water bath, the reactant mixture is neutralized with AcOH, used EtOAc dilutes, and uses saturation NaHCO₃It is dried with salt water washing and with sodium sulfate.By residue over silica gel column chromatography purification (0- The hexane solution of 100% ethyl acetate), intermediate 2f (tri- step of 1.0g, 59% Jing) is obtained, which is white solid.

¹H NMR (400MHz, CDCl₃) δ 9.40 (s, 1H), 8.84 (s, 1H), 8.13-7.97 (m, 3H), 7.73-7.61 (m, 1H), 7.6-7.47 (m, 2H), 5.55 (dd, J=7.9,5.5Hz, 0.5H), 5.49-5.30 (m, 1.5H), 4.76 (dd, J =5.4,2.6Hz, 1H), 3.94 (d, J=12.1Hz, 1H), 3.85 (d, J=12.0Hz, 1H), 3.70 (d, J=7.6Hz, 1H), 3.67 (d, J=7.6Hz, 1H), 0.96 (s, 9H), 0.19-0.14 (m, 6H).¹⁹F NMR (376MHz, CDCl₃)δ- 202.47 (dd, J=53.2,14.9Hz).MS m/z=534 [M+1].

Intermediate 2g-N- (7- ((2S, 3S, 4R, 5S) -5- ((double (4- methoxyphenyls) (phenyl) methoxyl groups) methyl) - 4- ((t-Butyldimethylsilyl) epoxide) -3- fluoro- 5- (hydroxymethyl) tetrahydrofuran -2- bases) thieno [3,2-d] pyrimidine - 4- yls) Benzoylamide

At 0 DEG C, using syringe pump, to intermediate 2f (1.0g, 1.94mmol) and triethylamine (0.7mL) in dichloromethane (40mL) DMTrCl (984mg, 2.90mmol) is slowly added in the solution in and continues 1h.After adding, by the reaction by adding Methanol (2mL) is quenched and by the mixture dchloromethane, is washed with water and saturation water sodium bicarbonate solution, use sodium sulfate It is dried and concentrating under reduced pressure.By residue over silica gel column chromatography purification (hexane solution of 0-70% ethyl acetate), intermediate is obtained 2g (660mg) simultaneously reclaims initiation material intermediate 2f (340mg).The starting intermediates 2f (340mg) for being reclaimed is again placed in Under identical reaction condition and isolate extra intermediate 2g (1.0g altogether, 64%), which is white solid.

MS m/z=836 [M+1].

Intermediate 2h-N- (7- ((2S, 3S, 4R, 5R) -5- ((double (4- methoxyphenyls) (phenyl) methoxyl groups) methyl) - 4- ((t-Butyldimethylsilyl) epoxide) -5- (((t-Butyldimethylsilyl) epoxide) methyl) -3- fluorine tetrahydrofuran -2- Base) thieno [3,2-d] pyrimidine-4-yl) Benzoylamide

Intermediate 2g (1.0g, 1.20mmol) is dissolved in DMF (10mL).Add imidazoles (244mg, 3.59mmol) and TBSCl (270mg, 1.79mmol).Gained mixture is stirred at room temperature into 2h and methanol (2mL) is added.Gained mixture is used EtOAc dilutes, and is washed with water and sodium bicarbonate solution, is dried with sodium sulfate and concentrated in vacuo.By gained residue over silica gel post Chromatogram purification (hexane solution of 0-70% ethyl acetate), (1.0g, 88%), which is white to the intermediate 2h for being protected completely Solid.

MS m/z=950 [M+1].

Intermediate 2i-N- (7- ((2S, 3S, 4R, 5R) -4- ((t-Butyldimethylsilyl) the epoxide) -5- (((tert-butyl groups two Methylsilyl) epoxide) methyl) -3- fluoro- 5- (hydroxymethyl) tetrahydrofuran -2- bases) thieno [3,2-d] pyrimidine-4-yl) benzene Methanamide

Intermediate 2h (1.0g, 1.05mmol) is dissolved in dichloromethane (15mL) and 0 DEG C is cooled to.It is slowly added to PTSA The solution of (200mg, 1.05mmol) in MeOH (5mL) continues 5min, and sodium bicarbonate solution is then added when being stirred vigorously (5mL).After with dchloromethane, mixture salt water washing is dried with sodium sulfate and concentrated in vacuo.Gained residue With silica gel chromatography (hexane solution of 0-60% ethyl acetate), obtain intermediate 2i, its be white solid (570mg, 84%).

MS m/z=648 [M+1].

Intermediate 2j-N- (7- ((2S, 3S, 4R, 5R) -4- ((t-Butyldimethylsilyl) the epoxide) -5- (((tert-butyl groups two Methylsilyl) epoxide) methyl) the fluoro- 5- formoxyls tetrahydrofuran -2- bases of -3-) thieno [3,2-d] pyrimidine-4-yl) benzoyl Amine

In room temperature, to intermediate 2i (570mg, 0.88mmol) and EDCI (506mg, 2.64mmol) in toluene-DMSO (2: Pyridine (0.1mL, 1.24mmol) and TFA (0.05mL, 0.65mmol) are continuously added in suspension in 4mL).Gained is mixed Thing is stirred at room temperature 1h, with diluted ethyl acetate, with sodium bicarbonate aqueous solution and salt water washing, is dried with sodium sulfate and vacuum is dense Contracting, obtains intermediate 2j (570mg), is directly used in next step.

MS m/z=646 [M+1].

Intermediate 2k-N- (7- ((2S, 3S, 4R, 5R) -4- ((t-Butyldimethylsilyl) the epoxide) -5- (((tert-butyl groups two Methylsilyl) epoxide) methyl) the fluoro- 5- of -3- ((E)-(oxyimino) methyl) tetrahydrofuran -2- bases) thieno [3,2-d] Pyrimidine-4-yl) Benzoylamide

In room temperature, hydroxylamine hydrochloride is added in solution of the intermediate 2j (570mg, rough) in pyridine (5mL) (92mg, 1.32mmol).Gained mixture is stirred at room temperature into 1h, with diluted ethyl acetate, salt water washing is used, it is dry with sodium sulfate It is dry and concentrated in vacuo.Gained residue over silica gel column chromatography purification (hexane solution of 0-80% ethyl acetate), obtains intermediate (500mg, 85%), which is white solid to 2k.

MS m/z=661 [M+1].

Intermediate 2l-N- (7- ((2S, 3S, 4R, 5R) -4- ((t-Butyldimethylsilyl) the epoxide) -5- (((tert-butyl groups two Methylsilyl) epoxide) methyl) -5- cyano group -3- fluorine tetrahydrofuran -2- bases) thieno [3,2-d] pyrimidine-4-yl) Benzoylamide

In room temperature, to intermediate 2k (500mg, 0.76mmol) in MeCN-THF (10:CDI is added in solution in 5mL) (430mg, 2.65mmol).Gained mixture is stirred at room temperature into 4h, with diluted ethyl acetate, salt water washing is used, is used sodium sulfate It is dry and concentrated in vacuo.Gained residue over silica gel column chromatography purification (hexane solution of 0-80% ethyl acetate), obtains centre (480mg, 99%), which is vitreous solid to body 2l.

¹H NMR (400MHz, CDCl₃) δ 9.40 (s, 1H), 8.81 (s, 1H), 8.22 (d, J=1.0Hz, 1H), 8.09- 8.03 (m, 2H), 7.71-7.63 (m, 1H), 7.57 (dd, J=8.5,7.0Hz, 2H), 5.80 (dt, J=24.4,1.4Hz, 1H), 5.20 (ddd, J=54.4,4.4,1.8Hz, 1H), 4.72 (dd, J=20.4,4.4Hz, 1H), 4.16 (d, J= 11.3Hz, 1H), 3.93 (d, J=11.2Hz, 1H), 0.96 (s, 9H), 0.90 (s, 9H), 0.12 (m, 12H).¹⁹F NMR (376MHz, CDCl₃) δ -191.15 to -191.55 (m).MS m/z=643 [M+1].

Intermediate 2m-N- (7- (fluoro- 4- hydroxyls -5- (hydroxymethyl) tetrahydrofurans of (2S, 3R, 4R, 5R) -5- cyano group -3- - 2- yls) thieno [3,2-d] pyrimidine-4-yl) Benzoylamide

In room temperature, acetic acid is added in solution of the intermediate 2l (480mg, 0.75mmol) in THF (10mL) (0.047mL, 0.82mL) is subsequently adding the THF solution (0.82mL, 0.82mmol) of 1M TBAF.By gained mixture in room temperature Stirring 15h is simultaneously concentrated in vacuo.By gained residue over silica gel column chromatography purification (the DCM solution of 0-7%MeOH), intermediate is obtained (300mg, 97%), which is syrup to 2m.

MS m/z=415 [M+1].

Embodiment 2- (2R, 3R, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) the fluoro- 3- hydroxyls -2- of -4- (hydroxymethyl) tetrahydrofuran -2- formonitrile HCNs

Intermediate 2m (300mg, 0.72mmol) is dissolved in the methanol solution (30mL) of 7M amine and is stirred at room temperature.24h Afterwards, will be the reactant mixture concentrated in vacuo and by gained residue over silica gel column chromatography purification (the DCM solution of 0-50%MeOH), (90mg, 40%), which is white solid to obtain embodiment 2.Starting intermediates 2m (120mg) has been reclaimed also.

¹H NMR (400MHz, CD₃OD) δ 8.37 (s, 1H), 8.14 (d, J=0.9Hz, 1H), 5.67 (ddd, J=23.6, 2.5,1.0Hz, 1H), 5.23 (ddd, J=54.4,4.5,2.5Hz, 1H), 4.65 (dd, J=19.8,4.5Hz, 1H), 4.04 (d, J=12.2Hz, 1H), 3.89 (d, J=12.2Hz, 1H).¹⁹F NMR (376MHz, CD₃OD) δ -195.68 (ddd, J= 54.4,23.7,19.8Hz).MS m/z=311 [M+1].

Double (benzyl epoxide) -5- ((benzyl epoxide) methyl) -2- (the 4- phenoxy group thiophenes of intermediate 3b- (3R, 4R, 5R) -3,4- Fen simultaneously [3,2-d] pyrimidin-7-yl) tetrahydrofuran -2- alcohol

To intermediate 3a (being purchased from Carbosynth, 6.8g, 16.27mmol) and intermediate 1b (5g, 16.3mmol) in THF (100mL) in the solution in, the hexane solution (7.2mL, 17.9mmol) of Deca 2.5M n-BuLi is into the reactant mixture, Internal temperature is kept to be less than -60 DEG C simultaneously.After 2h, the hexane solution (1mL) of the extra 2.5M n-BuLis of Deca.Again after 2h, Deca acetic acid (2mL, 35.8mmol), obtains pH=3.Remove cooling bath and stir 10 minutes.Diluted with ethyl acetate (100mL) And use saturation NaHCO₃(aq) (50mL) wash, then (50mL) washed with saturation NaCl (aq).Use anhydrous Na₂SO₄Drying is organic Thing concentrating under reduced pressure.With silica column purification (hexane solution of 0-40% ethyl acetate), obtain crude intermediate 3b (9g, 85%).

MS m/z=647.0 [M+1].

Intermediate 3c-7- (double (benzyl epoxide) -5- ((benzyl epoxide) methyl) the tetrahydrochysene furans of (2S, 3S, 4R, 5R) -3,4- Mutter -2- bases) -4- phenoxy group thieno [3,2-d] pyrimidines

Crude intermediate 3b (9g, 13.9mmol) is dissolved in the anhydrous DCM of 90mL and under 0 DEG C of argon by reaction mixing Thing is stirred in ice bath.Deca triethyl silicane (5.6mL, 34.8mmol), then Deca boron trifluoride diethyl ether (2.6mL, 20.9mmol).The reactant mixture is stirred 60 minutes and warms to room temperature the reactant mixture at 0 DEG C.After 16h, add Extra triethyl silicane (1.2mL) and boron trifluoride diethyl ether (870uL).After 20h, will be the reactant mixture cold in ice bath But to 0 DEG C and Deca TEA (6.8mL, 48.7mmol).Then to by the reactant mixture concentrating under reduced pressure.Residue is dissolved in into second In acetoacetic ester (200mL) and use saturation NaHCO₃(aq) (50mL) wash, then (50mL) washed with saturation NaCl (aq).It is organic Anhydrous Na is used mutually₂SO₄It is dried and concentrating under reduced pressure.By crude residue with silica gel chromatography (0-20-30% ethyl acetate Hexane solution), obtain intermediate 3c (2.98g, 34%).

¹H NMR (400MHz, CDCl₃) δ 8.73 (s, 1H), 8.11 (s, 1H), 7.55-7.41 (m, 4H), 7.41-7.19 (m, 16H), 5.70 (s, 1H), 4.95 (s, 2H), 4.67-4.51 (m, 3H), 4.50-4.41 (m, 2H), 4.28 (m, 1H), 4.23 (m, 1H), 3.98 (dd, J=10.8,2.8Hz, 1H), 3.73 (dd, J=10.8,3.2Hz, 1H).MS m/z=631.2 [M+ 1]。

Intermediate 3d-7- (double (benzyl epoxide) -5- ((benzyl epoxide) methyl) the tetrahydrochysene furans of (2S, 3S, 4R, 5R) -3,4- Mutter -2- bases) thieno [3,2-d] pyrimidine -4- amine

In sealing container, by intermediate 3c (2.98g, 4.7mmol) be dissolved in 25mL acetonitriles and with 30% hydrogen-oxygens of 25mL Change ammonium salt solution mixing and the reactant mixture is heated to into 80 DEG C.After 16h, 30% Ammonia (15mL) is added and by institute Obtain mixture 24h are stirred at 90 DEG C.Add extra acetonitrile (15mL) and gained mixture is stirred 4 days at 90 DEG C.This is anti- Answer mixture to be cooled to RT, saturation NaCl solution washing (3 ×) is diluted and used with EtOAc.By organic layer anhydrous sodium sulfate It is dried and concentrating under reduced pressure.By crude residue with silica column purification (hexane solution of 0-50% ethyl acetate), intermediate is obtained 3d (1.4g, 56%)

¹H NMR (400MHz, CDCl₃) δ 7.95 (s, 1H), 7.50-7.16 (m, 16H), 5.62 (s, 1H), 4.93 (s, 2H), 4.66-4.51 (m, 2H), 4.47 (m, 1H), 4.41 (m, 1H), 4.27 (m, 1H), 4.17 (s, 1H), 4.14-4.08 (m, 1H), 3.97 (dd, J=10.8,2.7Hz, 1H), 3.71 (dd, J=10.7,3.0Hz, 1H).MS m/z=554.2 [M+1].

Intermediate 3e- (2S, 3R, 4S, 5R) -2- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) -5- (hydroxymethyl) Tetrahydrofuran -3,4- glycol

Intermediate 3d (1.4g, 2.5mmol) is dissolved in the anhydrous DCM of 3mL and in -78 DEG C of stirred under Ar atmosphere.Deca 1M The DCM solution (8.8mL, 8.8mmol) of boron chloride.The reactant mixture is stirred into 2h and extra 1M boron chlorides are added DCM solution (1.25mL).After 1h, 1M triethylamine bicarbonate solutions (40mL) is disposably added in the reactant mixture and incited somebody to action Gained mixture is diluted with acetonitrile (50mL).The reactant mixture is slowly warmed to room temperature and concentrating under reduced pressure, obtains rough solid Body.The solid is suspended in ethyl acetate and gained mixture is stirred into 30min.Solvent is poured off and does solid vacuum It is dry, intermediate 3e (714mg) is obtained, next reaction is directly used in and need not be further purified.

MS m/z=284.1 [M+1].

Intermediate 3f- ((3aR, 4R, 6S, 6aS) -6- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) -2,2- dimethyl Tetrahydrofuran simultaneously [3,4-d] [1,3] Dioxol-4 -yl) methanol

Intermediate 3e (714mg, 2.52mmol) is dissolved in 50mL acetone and is stirred at room temperature.Add 2,2- dimethoxys Propane (619uL, 5.04mmol), then Deca methanesulfonic acid (245uL, 3.78mmol).After 2h, extra 2,2- dimethoxies are added Base propane (620uL) and methanesulfonic acid (163uL).After 20h, extra 2,2-dimethoxypropane (1.2mL) and methanesulfonic acid are added (163uL).After 24h, extra 2,2-dimethoxypropane (1.2mL) and methanesulfonic acid (163uL) are added.After 24h, add extra 2,2- dimethoxy propanes (1.2mL).After 24h, the reactant mixture ethyl acetate (100mL) is diluted and adds saturation Sodium bicarbonate aqueous solution, obtains pH=8.By organic extract salt water washing, with anhydrous sodium sulfate drying and concentrating under reduced pressure. Gained gel residue is suspended in hexane and stirs 2h.The solid is collected and washed with hexane, intermediate 3f is obtained (720mg, 88%).

¹H NMR (400MHz, CD₃OD) δ 8.52 (s, 1H), 8.30 (s, 1H), 5.17 (d, J=5.9Hz, 1H), 4.95- 4.91 (m, 1H), 4.80 (t, J=6.1Hz, 1H), 4.36 (q, J=2.5Hz, 1H), 3.88 (dd, J=2.6,1.0Hz, 2H), 1.62 (s, 3H), 1.37 (s, 3H).MS m/z=324.1 [M+1].

Intermediate 3g-7- ((3aS, 4S, 6R, 6aR) -6- (((t-Butyldimethylsilyl) epoxide) methyl) -2,2- diformazans Base tetrahydrofuran simultaneously [3,4-d] [1,3] Dioxol-4 -yl) thieno [3,2-d] pyrimidine-4- amine

Intermediate 3f (720mg, 2.23mmol) is dissolved in 10mL dry DMFs.Add imidazoles (395mg, 5.8mmol) and Tert-butyl chloro-silicane (436mg, 2.89mmol).After 3h, extra imidazoles (395mg) and tert-butyldimethylsilyl chloride are added Silane (436mg).After 16h, the reactant mixture ethyl acetate (75mL) is diluted and uses saturation NaHCO₃(aq) wash right Salt water washing is used afterwards.By the organic layer anhydrous Na₂SO₄It is dried and concentrating under reduced pressure.Will be the crude residue pure with silica gel column chromatography Change (hexane solution of 0-50% ethyl acetate), obtain intermediate 3g (1g, 99%)

¹H NMR (400MHz, CDCl₃) δ 8.05 (s, 1H), 7.91 (s, 1H), 5.57-5.44 (m, 3H), 4.97 (m, 1H), 4.80 (m, 1H), 4.26 (m, 1H), 3.98-3.74 (m, 2H), 1.67 (s, 3H), 1.41 (s, 3H), 0.92 (s, 9H), 0.10 (s, 6H).MS m/z=438.1 [M+1].

Intermediate 3h- (7- ((3aS, 4S, 6R, 6aR) -6- (((t-Butyldimethylsilyl) epoxide) methyl) -2,2- two Methyltetrahydrofuran simultaneously [3,4-d] [1,3] Dioxol-4 -yl) thieno [3,2-d] pyrimidine-4-yl) carbamic acid uncle Butyl ester

Intermediate 3g (976mg, 2.23mmol) is dissolved in 12mL THF.It is subsequently adding TEA (311uL, 2.23mmol) With Bis(tert-butoxycarbonyl)oxide (583mg, 2.68mmol), DMAP (136mg, 1.12mmol) is subsequently adding.After 1h, add extra Bis(tert-butoxycarbonyl)oxide (583mg) and DMAP (136mg).Again after 2h, the reactant mixture is diluted with ethyl acetate (75mL) And washed with 5% aqueous citric acid solution, then use salt water washing.By organic layer anhydrous Na₂SO₄It is dried and concentrating under reduced pressure.Will be thick During residue processed is dissolved in MeOH and 1N NaOH (aq) are added to realize pH=12.After 16h, extra 1N NaOH (aq) are added, Obtain pH=13.Again after 14h, the reactant mixture ethyl acetate (75mL) is diluted and with salt water washing (3 ×).Will be organic Layer anhydrous Na₂SO₄It is dried and concentrating under reduced pressure.By crude intermediate 3h, (83%) 1g is directly used in next reaction and need not enter One step purification.

MS m/z=538.0 [M+1], 536.3 [M-1].

(((3aS, 4S, 6R, 6aR) -6- (hydroxymethyl) -2,2- dimethyl-tetrahydrofurans are simultaneously [3,4-d] for 7- for intermediate 3i- [1,3] Dioxol-4 -yl) thieno [3,2-d] pyrimidine-4-yl) t-butyl carbamate

Intermediate 3h (1g, 1.86mmol) is dissolved in 15mL THF.Then disposably add three water of tetrabutyl ammonium fluoride Compound (880mg, 2.79mmol).After 2h, extra 4-butyl ammonium fluoride trihydrate (293mg, 0.5 equivalent) is added.16h Afterwards, the reactant mixture ethyl acetate (75mL) is diluted and uses saturation NaHCO₃(aq) wash, then use salt water washing.Will Organic layer anhydrous Na₂SO₄It is dried and concentrating under reduced pressure.By the crude residue with silica column purification (0-50% ethyl acetate oneself Alkane solution), obtain intermediate 3i (648mg, 82%).

¹H NMR (400MHz, CDCl₃) δ 8.81 (s, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 5.10 (m, 3H), 4.50 (s, 1H), 3.99 (dt, J=12.3,1.7Hz, 1H), 3.83 (dt, J=12.3,1.8Hz, 1H), 1.68 (s, 3H), 1.65 (s, 9H), 1.40 (s, 3H).MS m/z=424.0 [M+1], 422.2 [M-1].

Intermediate 3j- (7- (double (the hydroxymethyl) -2,2- dimethyl-tetrahydrofurans of (3aS, 4S, 6aS) -6,6- simultaneously [3,4- D] [1,3] Dioxol-4 -yl) thieno [3,2-d] pyrimidine-4-yl) t-butyl carbamate

Under nitrogen atmosphere, intermediate 3i (551mg, 1.3mmol) is dissolved in the anhydrous DMSO of 7mL.Then it is disposable to add EDCI (374mg, 1.95mmol), is subsequently adding pyridinium trifluoroacetate (126mg, 0.65mmol).After 1h, extra EDCI is added (374mg, 1.95mmol).After 1h, extra EDCI (374mg, 1.95mmol) is added.Again after 1h, the reactant mixture is used Ethyl acetate (75mL) dilutes and uses saturation NaHCO₃(aq) wash, then use salt water washing.By organic layer anhydrous Na₂SO₄Have Machine is dried and concentrating under reduced pressure.The crude residue is dissolved in 10mL dioxs and 1mL water.Add 37% formalin (774uL, 10.4mmol), is subsequently adding NaOH (aq) solution (62mg, 1.56mmol are in 500uL water).After 1h, this is reacted Mixture ethyl acetate (75mL) dilutes and with salt water washing (3 ×).By organic layer anhydrous Na₂SO₄It is dried and reduces pressure and is dense Contracting.Then the crude residue is dissolved in MeOH (50mL) and the stirring in ice bath.Then disposably add sodium borohydride (98mg, 2.6mmol).After 30min, extra sodium borohydride ((98mg, 2.6mmol) is added.It is after extra 30min, this is anti- Mixture ethyl acetate (75mL) is answered to dilute and use saturation NaHCO₃And salt water washing (aq).By organic layer anhydrous Na₂SO₄ Organic drying concentrating under reduced pressure.By crude residue with silica gel chromatography (hexane solution of 0-50% ethyl acetate), obtain To intermediate 3j (360mg, 61%)

¹H NMR (400MHz, CDCl₃) δ 8.80 (s, 1H), 8.07 (s, 1H), 7.99 (d, J=3.0Hz, 1H), 5.21 (m, 2H), 5.15 (m, 1H), 3.93 (d, J=11.9Hz, 2H), 3.81 (m, 2H), 1.69 (s, 3H), 1.61 (s, 9H), 1.41 (s, 3H).MS m/z=454.0 [M+1], 452.2 [M-1].

Intermediate 3k- (7- ((3aS, 4S, 6S, 6aS) -6- ((double (4- methoxyphenyls) (phenyl) methoxyl groups) methyl) - 6- (hydroxymethyl)-2,2- dimethyl-tetrahydrofurans simultaneously [3,4-d] [1,3] Dioxol-4 -yl) thieno [3,2-d] Pyrimidine-4-yl) t-butyl carbamate

Intermediate 3j (360mg, 0.79mmol) is dissolved in the anhydrous DCM of 10mL and the stirring in ice bath under nitrogen atmosphere. TEA (220uL, 1.58mmol) is added, DMTrCl (401mg, 1.19mmol) is subsequently adding.After 90min, extra TEA is added (110uL) with DMTrCl (134mg).After 2h, the reactant mixture ethyl acetate (50mL) is diluted and uses saturation NaHCO₃ And salt water washing (aq).By organic layer anhydrous Na₂SO₄It is dried and concentrating under reduced pressure.By crude residue silica gel chromatography (hexane solution of 0-30% ethyl acetate), obtain intermediate 3k (453mg, 76%).

¹H NMR (400MHz, CDCl₃) δ 8.77 (d, J=3.6Hz, 1H), 7.97 (s, 1H), 7.78 (s, 1H), 7.58- 7.49 (m, 1H), 7.41 (m, 2H), 7.37-7.26 (m, 3H), 7.26-7.14 (m, 2H), 6.91-6.77 (m, 4H), 5.25- 5.19 (m, 1H), 5.19-5.12 (m, 2H), 4.96-4.85 (m, 1H), 4.07-3.88 (m, 2H), 3.88-3.72 (m, 6H), 3.66-3.56 (m, 1H), 3.19 (d, J=9.4Hz, 1H), 1.60 (m, 12H), 1.40 (d, J=3.3Hz, 3H).MS m/z= 778.1 [M+Na], 754.2 [M-1].

Intermediate 3l- (7- ((3aS, 4S, 6R, 6aS) -6- ((double (4- methoxyphenyls) (phenyl) methoxyl groups) methyl) - 6- (((t-Butyldimethylsilyl) epoxide) methyl) -2,2- dimethyl-tetrahydrofurans simultaneously [3,4-d] [1,3] dioxane penta Alkene -4- bases) thieno [3,2-d] pyrimidine-4-yl) t-butyl carbamate

Intermediate 3k (453mg, 0.6mmol) is dissolved in 5mL dry DMFs.It is subsequently adding imidazoles (123mg, 1.8mmol) With TBSCl (136mg, 0.9mmol).After 2h, add extra imidazoles (123mg, 1.8mmol) and TBSCl (136mg, 0.9mmol).After 2h, the reactant mixture ethyl acetate (50mL) is diluted and uses saturation NaHCO₃And salt water washing (aq). By organic layer anhydrous Na₂SO₄It is dried and concentrating under reduced pressure.By crude residue silica gel chromatography (0-20% ethyl acetate Hexane solution), obtain intermediate 3l (519mg, 99%)

MS m/z=892.1 [M+Na], 868.3 [M-1].

Intermediate 3m- (7- ((3aS, 4S, 6R, 6aS) -6- (((t-Butyldimethylsilyl) epoxide) methyl) -6- (hydroxyls Methyl)-2,2- dimethyl-tetrahydrofurans simultaneously [3,4-d] [1,3] Dioxol-4 -yl) thieno [3,2-d] pyrimidine-4- Base) t-butyl carbamate

Intermediate 3l (519mg, 0.60mmol) is dissolved in 6mL DCM and the stirring in ice bath under 0 DEG C of blanket of nitrogen.Will Solution of the PTSA (125mg, 0.66mmol) in 6mL MeOH is dropped in the reaction.After 1h, by the reactant mixture second Acetoacetic ester (50mL) dilutes and uses saturation NaHCO₃And salt water washing (aq).By organic layer anhydrous Na₂SO₄It is dried and reduces pressure and is dense Contracting.By crude residue with silica gel chromatography (hexane solution of 0-50% ethyl acetate), obtain intermediate 3m (254mg, 75%).

¹H NMR (400MHz, CDCl₃) δ 8.86 (dd, J=4.7,1.6Hz, 1H), 8.16-8.08 (m, 1H), 8.01 (s, 1H), 5.57 (d, J=4.4Hz, 1H), 5.07 (dd, J=6.4,4.1Hz, 1H), 4.87 (t, J=6.2Hz, 1H), 4.00- 3.78 (m, 4H), 1.71 (d, J=5.4Hz, 3H), 1.61 (d, J=5.8Hz, 9H), 1.42 (d, J=5.4Hz, 3H), 0.98- 0.87 (m, 9H), 0.10 (m, 6H).MS m/z=568.0 [M+1], 566.2 [M-1].

Intermediate 3n- (7- ((3aS, 4S, 6R, 6aS) -6- (((t-Butyldimethylsilyl) epoxide) methyl) -6- cyano group - 2,2- dimethyl-tetrahydrofurans simultaneously [3,4-d] [1,3] Dioxol-4 -yl) thieno [3,2-d] pyrimidine-4-yl) amino T-butyl formate

Intermediate 3m (100mg, 0.176mmol) is dissolved in the anhydrous DMSO of 3mL and is stirred under nitrogen atmosphere.It is disposable to add Enter EDCI (51mg, 0.26mmol), be subsequently adding pyridinium trifluoroacetate (17mg, 0.088mmol).After 45min, add extra EDCI (51mg, 0.26mmol).After 30min, extra EDCI (75mg) is added.After 30min, extra EDCI is added (75mg).After 30min, the reaction ethyl acetate (50mL) is diluted and uses saturation NaHCO₃And salt water washing (aq).Should Organic layer anhydrous Na₂SO₄It is dried and concentrating under reduced pressure.The crude residue is dissolved in 5mL anhydrous pyridines.It is subsequently adding azanol Hydrochlorate (18mg, 0.264mmol).After 90min, by the reactant mixture concentrating under reduced pressure.Residue is dissolved in into ethyl acetate (50mL) in and by gained mixture saturation NaHCO₃And salt water washing (aq).By organic layer anhydrous Na₂SO₄It is dried and subtracts Pressure concentration.Then the crude residue is dissolved in 5mL acetonitriles.It is subsequently adding CDI (43mg, 0.264mmol) and this is reacted Stirring 30min.It is subsequently adding extra CDI (45mg) and the reactant mixture is stirred 30 minutes.It is subsequently adding extra CDI (45mg) and by the reactant mixture stir 30 minutes.Then the reactant mixture ethyl acetate (50mL) is diluted and with full And NaHCO₃And salt water washing (aq).Then by the organic layer anhydrous Na₂SO₄It is dried and concentrating under reduced pressure.By the crude residue With silica gel chromatography (hexane solution of 0-30% ethyl acetate), obtain intermediate 3n (88mg, 89%).

¹H NMR (400MHz, CDCl₃) δ 8.81 (dd, J=4.1,1.6Hz, 1H), 8.14-7.93 (m, 1H), 5.68 (dt, J=3.4,2.1Hz, 1H), 5.16 (m, 1H), 5.09-4.99 (m, 1H), 4.09-3.96 (m, 2H), 1.87-1.77 (m, 3H), 1.67-1.54 (m, 9H), 1.47-1.36 (m, 3H), 1.01-0.88 (m, 9H), 0.20-0.07 (m, 6H).MS m/z=563.0 [M+1], 561.2 [M-1].

Embodiment 3- (2R, 3S, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) -3,4- dihydroxy -2- (hydroxymethyl) tetrahydrofuran -2- formonitrile HCNs

Intermediate 3n (88mg, 0.156mmol) is dissolved in into 5mL TFA/H2O solution (1:1).After 20h, the reaction is mixed Thing concentrating under reduced pressure.The crude residue is dissolved in 20mM triethylamine bicarbonate solutions and with preparative-HPLC purification (2- The aqueous solution of 70% acetonitrile), obtain embodiment 3 (39mg, 81%).

¹H NMR (400MHz, CD₃OD) δ 8.41 (s, 1H), 8.14 (s, 1H), 5.27 (d, J=7.2Hz, 1H), 4.47 (dd, J=7.2,5.4Hz, 1H), 4.37 (d, J=5.4Hz, 1H), 4.04-3.85 (m, 2H).MS m/z=309.1 [M+1], 307.1[M-1]。

Embodiment 4- (2R, 3R, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) -2- azido -4- are chloro- 2- (hydroxymethyl) tetrahydrofuran -3- alcohol

Intermediate 4b- trifluoromethanesulfonic acid (3S, 4R, 5R) -4- (benzyl epoxide) -5- ((benzyl epoxide) methyl) -2- methoxies Base tetrahydrofuran -3- base esters.

In ice bath, to intermediate 4a (be purchased from Combi-Blocks, 1.4g, 0.07mmol) in dichloromethane (30mL) and The DCM solution (12.2mL) of 1M Trifluoromethanesulfonic anhydrides is added to continue 15min in solution in pyridine (15mL).By the mixture 30min is stirred in ice bath, with dchloromethane, NaHCO is used₃Solution washing, is dried with sodium sulfate and is steamed with toluene altogether Send out.By the crude residue with silica gel chromatography (hexane solution of EtOAc 0-40%), obtain compound 4b (1.2g, 62%), which is syrup.

Intermediate 4c- (2R, 3R, 4R) -3- (benzyl epoxide) -2- ((benzyl epoxide) methyl) -4- chloro-5-methoxyl tetrahydrochysenes Furan.

By the mixing of compound 4b (1.9g, 4.00mmol) and LiCl (845mg, 20.00mmol) in HMPA (12mL) Thing is stirred at room temperature 1h, is diluted with EtOAc, is washed with saline (4x), is dried with sodium sulfate, concentrated in vacuo, then by residue With silica gel chromatography (hexane solution of EtOAc 0-30%), compound 4c is obtained, which is anomeric mixture (800mg comparatively fast mobile isomer, the isomer that 300mg is moved more slowly), which is syrup (76%)：For relatively slow mobile end Base isomer.

¹H NMR (400MHz, CDCl₃) δ 7.47-7.07 (m, 10H), 5.02 (d, J=4.3Hz, 1H), 4.80 (d, J= 12.6Hz, 1H), 4.57 (d, J=12.6Hz, 1H), 4.50 (d, J=12.1Hz, 1H), 4.42 (d, J=12.1Hz, 1H), 4.24 (q, J=3.7Hz, 1H), 4.18 (dd, J=6.7,4.3Hz, 1H), 3.96 (dd, J=6.7,3.9Hz, 1H), 3.51 (s, 4H), 3.36 (dd, J=10.7,3.7Hz, 1H).

Intermediate 4d- (3R, 4R, 5R) -4- (benzyl epoxide) -5- ((benzyl epoxide) methyl) -3- chlorine dihydrofuran -2 (3H) -one.

Compound 4c (3.0g, 8.27mmol) is dissolved in TFA (10mL)-water (10mL).By gained mixture in room temperature Stirring 16h, it is in 50 DEG C of heating 4h and concentrated in vacuo.By gained residue over silica gel column chromatography purification (EtOAc 0-50% oneself Alkane solution), (2.1g, 72%), which is syrup to obtain inner hemiacetal intermediate.Then by the inner hemiacetal intermediate (2.1g, 6.02mmol) it is dissolved in dichloromethane (40mL) and is processed with 4A MS (5g) and pyridinium dichromate (6.80g, 18.06mmol). Gained mixture is stirred at room temperature into 4h, is then filtered and concentrating under reduced pressure by Celite pad.Residue is carried out into silicagel column color Spectrum purification (hexane solution of EtOAc 0-30%), (1.7g, 81%), which is syrup to obtain compound 4d.

¹H NMR (400MHz, CDCl₃) δ 7.42-7.23 (m, 10H), 4.76 (d, J=11.7Hz, 1H), 4.70 (dd, J= 5.9,1.1Hz, 1H), 4.63-4.51 (m, 3H), 4.48 (d, J=11.9Hz, 1H), 4.32 (dd, J=5.8,3.7Hz, 1H), 3.76 (dd, J=11.3,2.4Hz, 1H), 3.62 (dd, J=11.3,2.6Hz, 1H).

Intermediate 4e- (3R, 4R, 5R) -4- (benzyl epoxide) -5- ((benzyl epoxide) methyl) -3- chloro- 2- (4- phenoxy groups Thieno [3,2-d] pyrimidin-7-yl) tetrahydrofuran -2- alcohol.

At -78 DEG C, to compound 4d (1.7g, 4.90mmol) and compound 1b (2.08g, 5.88mmol) in THF (40mL) in the solution in, Deca 1M BuLi (2.35mL, 5.88mmol) continues 30min.Gained mixture is stirred at -78 DEG C 30min.It is subsequently adding AcOH (2mL).Then the reactant mixture is diluted with EtOAc, it is with salt water washing and concentrated in vacuo.Will Residue over silica gel column chromatography purification (hexane solution of EtOAc 0-60%), obtain compound 4e (2.82g, 35%).

MS m/z 575[M+1]。

Intermediate 4f-7- ((2S, 3S, 4R, 5R) -4- (benzyl epoxide) -5- ((benzyl epoxide) methyl) -3- chlorine tetrahydrochysene furans Mutter -2- bases) -4- phenoxy group thieno [3,2-d] pyrimidines.

Compound 4e (2.0g, 1.74mmol) is suspended in DCM (20mL) and TES (5.56mL, 34.78mmol), so Heating BF3 etherates (1.12mL, 8.70mmol) under ice bath afterwards.Gained mixture is stirred at room temperature into 6h and the reaction is mixed Compound is neutralized with sodium bicarbonate solution in frozen water.Then the mixture is diluted with DCM, washes with water, be dried with sodium sulfate And it is concentrated in vacuo.Gained residue over silica gel column chromatography purification (hexane solution of EtOAc 0-50%), obtains compound 4f (460mg, 22%), which is white foam.

MS m/z 559[M+1]。

(4- phenoxy group thienos [3,2-d] is phonetic for chloro- 2- (the hydroxymethyl) -5- of intermediate 4g- (2R, 3R, 4R, 5S) -4- Pyridine -7- bases) tetrahydrofuran -3- alcohol.

In ice bath, the Deca in solution of the compound 4f (460mg, 0.53mmol, 64% purity) in DCM (5mL) Methanesulfonic acid (0.9mL, 13.16mmol).Gained mixture is stirred at room temperature into 15h, is neutralized with TEA, it is concentrated in vacuo and by remnants With silica gel chromatography (the DCM solution of MeOH 0-5%), (77mg, 39%), which is gray solid to thing to obtain compound 4g.

¹H NMR (400MHz, DMSO-d6) δ 8.72 (s, 1H), 7.99 (s, 1H), 7.48 (t, J=7.9Hz, 2H), 7.39-7.30 (m, 1H), 7.25 (dd, J=8.7,1.3Hz, 2H), 5.23 (d, J=10.0Hz, 1H), 4.97 (dd, J= 10.0,4.4Hz, 1H), 4.52 (d, J=4.4Hz, 1H), 4.38 (s, 1H), 3.99 (dd, J=12.7,1.9Hz, 1H), 3.79 (dd, J=12.7,1.4Hz, 1H).MS m/z 379[M+1].

(4- phenoxy group thienos [3,2-d] is phonetic for chloro- 2- (the iodo-methyl) -5- of intermediate 4h- (2S, 3R, 4R, 5S) -4- Pyridine -7- bases) tetrahydrofuran -3- alcohol.

In room temperature, to compound 4g (100mg, 0.264mmol), Ph₃P (104mg, 0.396mmol) and imidazoles (27mg, Iodine (101mg, 0.396mmol) is added in the mixture in THF (4mL) 0.396mmol).By the reactant mixture in room temperature Stirring 5h simultaneously adds NaHCO3 aqueous solutions (2mL).Then will be the mixture concentrated in vacuo and with silica gel chromatography (EtOAc The hexane solution of 0-60%), (97mg, 75%), which is white solid to obtain compound 4h.

MS m/z 489[M+1]。

Chloro- 2- (iodo-methyl) -5- (the 4- phenoxy group thienos of intermediate 4j- (2S, 3R, 4R, 5S) -2- azido -4- [3,2-d] pyrimidin-7-yl) tetrahydrofuran -3- alcohol.

Compound 4h (90mg, 0.184mmol) and DBU (0.165mL, 1.11mmol) are stirred at room temperature into 15h.Then will The reactant mixture is diluted with EtOAc, is washed with water, is dried with sodium sulfate and concentrated in vacuo, is obtained crude residue 4i, by which It is vacuum dried and is directly used in next reaction.

At 0 DEG C, in suspension of the Hydrazoic acid,sodium salt (127mg, 1.954mmol) in MeCN ICl (0.021mL, 0.421mmol).Gained mixture is stirred at room temperature into 30min and in 0 DEG C of Deca 4i (66mg, 0.184mmol) in acetonitrile (1mL) crude residue in.Gained mixture is stirred into 30min at 0 DEG C and sodium thiosulfate (0.2mL) is added.Then will The mixture stirs 10min, is diluted with EtOAc, uses salt water washing, is dried with sodium sulfate and concentrated in vacuo.By gained residue With silica gel chromatography (hexane solution of EtOAc 0-50%), (30mg, 31%, which is 1.3 to obtain compound 4j:1 isomery Body mixture), which is white solid.

MS m/z 530[M+1]。

Intermediate 4k-3- chlorobenzoic acids ((2R, 3R, 4R, 5S) -2- azido -4- chloro-3-hydroxyl -5- (4- phenoxy group thiophenes Fen simultaneously [3,2-d] pyrimidin-7-yl) tetrahydrofuran -2- bases) methyl ester.

By compound 4j (30mg, 0.057mmol), mCBA (22mg, 0.142mmol), 4-butyl ammonium hydrogen sulfate (20mg, 0.057mmol) cool down in ice bath with the mixture of dipotassium hydrogen phosphate (52mg, 0.227mmol), be then stirred vigorously lower addition MCPBA (51mg, 0.227mmol).Gained mixture is stirred in frozen water 3h and 1h is stirred at room temperature.Then add under ice bath Hot hypo solution (0.5mL).After 5min, the mixture is diluted with EtOAc, salt water washing is used, is dried with sodium sulfate And it is concentrated in vacuo.Gained residue over silica gel column chromatography purification (hexane solution of EtOAc 0-30%), obtains compound 4k (7mg, 22%), which is white solid.

¹H NMR (400MHz, CDCl₃) δ 8.65 (s, 1H), 8.04 (d, J=0.8Hz, 1H), 7.97 (t, J=1.8Hz, 1H), 7.90 (dt, J=7.9,1.3Hz, 1H), 7.54 (ddd, J=8.0,2.1,1.1Hz, 1H), 7.52-7.44 (m, 2H), 7.41-7.30 (m, 2H), 7.28-7.20 (m, 2H), 5.80 (d, J=3.4Hz, 1H), 5.16 (dd, J=6.7,3.4Hz, 1H), 5.00 (dd, J=11.1,6.8Hz, 1H), 4.77 (d, J=11.9Hz, 1H), 4.67 (d, J=11.9Hz, 1H).MS m/z 558[M+1]。

Embodiment 4- (2R, 3R, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) -2- azido -4- are chloro- 2- (hydroxymethyl) tetrahydrofuran -3- alcohol.

By the mixture of compound 4k (7mg, 0.013mmol), ammonium hydroxide solution,stronger (0.5mL) and acetonitrile (0.5mL) 48h is heated in 70 DEG C of sealed flasks.Then will be gained mixture concentrated in vacuo, purify in being dissolved in methanol (1mL) and with HPLC (aqueous solution of acetonitrile 0-30%, in 20min), (2.7mg, 63%), which is pale solid to obtain compound 4.

¹H NMR (400MHz, methanol-d4) δ 8.38 (s, 1H), 8.21 (s, 1H), 5.49 (d, J=9.4Hz, 1H), 4.95 (dd, J=9.4,4.8Hz, 1H), 4.45 (d, J=4.8Hz, 1H), 3.73 (d, J=12.1Hz, 1H), 3.54 (d, J= 12.1Hz, 1H).MS m/z=343 (M+1).

Triguaiacyl phosphate (TP) embodiment

Embodiment TP1- tetrahydrochysene triphosphoric acid ((2R, 3R, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) - The fluoro- 3- hydroxyl tetrahydrofurans -2- bases of 2- azido -4-) methyl ester

At 0 DEG C, to embodiment 1 (15mg, 0.046mmol) and NaHCO₃(10mg, 0.119mmol) is in trimethyl phosphate (0.6mL) solution in adds POCl₃(50mg, 0.326mmol).The reactant mixture is stirred into 6h at 0 DEG C.Ion exchange HPLC shows about 65% conversion.Add pyrophosphoric acid tri-n-butylamine salt (250mg, 0.688mmol) molten in MeCN (0.6mL) Liquid, is subsequently adding tri-n-butylamine (121mg, 0.65mmol).The reactant mixture is stirred into 0.5h at 0 DEG C.By three second of the reaction Amine buffered with bicarbonate aqueous solution (1M, 6mL) is quenched.The reactant mixture is stirred at room temperature into 0.5h, then concentration and water Coevaporation is twice.Residue is dissolved in into H₂O (5mL) is simultaneously loaded on ion exchange column, uses H₂O eluting, then with 10-35% tri- Ethamine bicarbonate buffer (1M)-H₂O eluting.By Product-level division simultaneously, concentration and H₂O coevaporations, obtain the material of about 20mg Material.The material is dissolved in into H₂O (1mL) is simultaneously processed with NaOH aqueous solutions (1N, 0.12mL), is concentrated into about 0.5mL and is used C-18 posts Purification, uses H₂O eluting.By Product-level division and and concentrate, obtain needed for triguaiacyl phosphate TP1, its be tetrasodium salt (14mg, 47%).

¹H NMR (400MHz, D₂O) δ 8.19 (s, 1H), 8.06 (s, 1H), 5.73 (d, J=24Hz, 1H), 5.06 (dd, J =55.6,4.4Hz, 1H), 4.63 (dd, J=28.0,4.4Hz, 1H), 4.19 (wide s, 2H).¹⁹F NMR (376MHz, D₂O)δ- 195.32 to -195.60 (m).³¹P NMR (162MHz, D₂O) δ -8.16 (d, J=48Hz, 1P), -14.10 (d, J=48Hz, 1P), -23.9 (t, J=48Hz, 1P).MS m/z=566.97 [M+1].

Embodiment TP2- tetrahydrochysene triphosphoric acid ((2R, 3R, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) - The fluoro- 3- hydroxyl tetrahydrofurans -2- bases of 2- cyano group -4-) methyl ester

(6mg, 53%) to make tetrasodium salt with embodiment TP1 similar mode, which uses embodiment 2 to make to embodiment TP2 For initiation material.

¹H NMR (400MHz, D₂O) δ 8.26 (s, 1H), 8.07 (s, 1H), 5.77 (d, J=24.8Hz, 1H), 5.16 (dd, J=54,4Hz, 1H), 4.75 (dd, J=26.0,4.0Hz, 1H), 4.4 (d, J=4.8Hz, 2H).¹⁹F NMR (376MHz, D₂O) δ -193.49 to -193.77 (m).³¹P NMR (162MHz, D₂O) δ -8.22 (d, J=48Hz, 1P), -14.45 (d, J=48Hz, 1P), -24.0 (t, J=48Hz, 1P).MS m/z=550.89 [M+1].

Embodiment TP3- tetrahydrochysene triphosphoric acid ((2R, 3S, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) - 2- cyano group -3,4- dihydroxytetrahydrofandn -2- bases) methyl ester

(3mg, 26%) to make tetrasodium salt with embodiment TP1 similar mode, which uses embodiment 3 to make to embodiment TP3 For initiation material.

¹H NMR (400MHz, D₂O) δ 8.22 (s, 1H), 8.08 (s, 1H), 5.4 (d, J=4.4Hz, 1H), 4.55 (d, J= 4.4Hz, 1H), 4.37 (dd, J=4.4,4.4Hz, 1H), 4.18-4.3 (m, 2H).³¹P NMR (162MHz, D₂O) δ -4.27 (d, J=48Hz, 1P), -10.44 (d, J=48Hz, 1P), -20.1 (t, J=48Hz, 1P).MS m/z=548.95 [M+1].

Embodiment TP4- tetrahydrochysene triphosphoric acid ((2R, 3R, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) - 2- azido -4- chloro-3-hydroxyl tetrahydrofuran -2- bases) methyl ester.

To make tetrasodium salt with embodiment TP1 similar mode, which uses embodiment 4 as initiation material to embodiment TP4.

¹H NMR (400MHz, D₂O) δ 8.28 (s, 1H), 8.24 (s, 1H), 5.76 (d, J=4.4Hz, 1H), 4.77 (d, J =4.4Hz, 1H), 4.70 (dd, J=4.8,4.8Hz, 1H), 4.20-4.10 (m, 2H).³¹P NMR (162MHz, D₂O)δ-4.85 (d, J=48.4Hz, 1P), -10.32 (d, J=48.4Hz, 1P), -20.44 (t, J=48.4Hz, 1P).MS m/z=582.88 [M+1]。

Embodiment PD1- (2S) -2- (((((2R, 3R, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) - The fluoro- 3- hydroxyl tetrahydrofurans -2- bases of 2- azido -4-) methoxyl group) (phenoxy group) phosphoryl) amino) ethyl propionate

Embodiment 1 (5.00mg, 15.3 μm of ol) is dissolved in NMP (0.2mL).Under room temperature under argon, THF is added (0.1mL), it is subsequently adding tert-butyl group magnesium chloride (THF solution of 1.0M, 0.024mL, 23 μm of ol).After 20min, intermediate is added The reaction is simultaneously mixed by solution of the PD1a (being prepared according to US20120009147A1,12.1mg, 30.7 μm of ol) in THF (0.1mL) Compound is warmed to 50 DEG C.After 23h, extra intermediate PD1a (12.1mg, 30.7 μm of ol) and tert-butyl group magnesium chloride (1.0M is added THF solution, 0.024mL, 23 μm of ol).After 5h, by gained mixture preparation HPLC direct purification (Phenominex Synergi 4u Hydro-RR150x 30mm posts, 40-100% acetonitrile/water gradients).Separate major diastereomer, (1.0mg, 20%), which is faint yellow solid to obtain embodiment PD1.

¹H NMR (400MHz, CDCl₃) δ 8.57 (s, 1H), 7.94 (s, 1H), 7.38-7.12 (m, 5H), 5.81 (d, J= 25.1Hz, 1H), 5.76 (wide s, 1H), 5.25 (dd, J=54.9,4.8Hz, 1H), 4.59 (wide d, J=24.4Hz, 1H), 4.45 (dd, J=11.2,7.2Hz, 1H), 4.34 (dd, J=11.2,7.1Hz, 1H), 4.21-4.08 (m, 2H), 4.02 (td, J= 8.9,6.8Hz, 1H), 3.83-3.72 (m, 1H), 1.36 (d, J=7.1Hz, 3H), 1.23 (t, J=7.1Hz, 3H).¹⁹F NMR (376MHz, D₂O) δ -193.64 (dt, J=54.4,24.4Hz).³¹P NMR (162MHz, CDCl₃)δ2.57(s).MS m/z= 581.90[M+1]。

Following compound, or its pharmaceutically acceptable salt are additionally provided, which is prepared using method disclosed in the present application：

A) (2R, 3R, 4R, 5S) -5- (4- amino -2- fluorine thieno [3,2-d] pyrimidin-7-yls) -2- azido -4- are fluoro- 2- (hydroxymethyl) tetrahydrofuran -3- alcohol：

B) (2R, 3R, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) chloro- 2- (hydroxyls of -2- azido -4- Ylmethyl) tetrahydrofuran -3- alcohol：

With

C) (2R, 3S, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) -2,4- diazido -2- (hydroxyls Methyl) tetrahydrofuran -3- alcohol：

D) (2R, 3S, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) -4- azido -3- hydroxyl -2- (hydroxymethyl) tetrahydrofuran -2- formonitrile HCNs：

E) (2R, 3R, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) fluoro- 2- (hydroxyls of -2- ethyl -4- Methyl) tetrahydrofuran -3- alcohol：

F) (2R, 3R, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) the chloro- 2- ethyls -2- (hydroxyls of -4- Methyl) tetrahydrofuran -3- alcohol：

G) (2R, 3S, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) -4- azido -2- ethyl -2- (hydroxymethyl) tetrahydrofuran -3- alcohol：

H) (2R, 3R, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) the fluoro- 2- of -2- (chloromethyl) -4- (hydroxymethyl) tetrahydrofuran -3- alcohol：

I) (2R, 3R, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) -4- chloro- 2- (chloromethyl) -2- (hydroxymethyl) tetrahydrofuran -3- alcohol：

With

J) (2R, 3S, 4R, 5S) -5- (4- aminothiophenes simultaneously [3,2-d] pyrimidin-7-yl) -4- azido -2- (chloromethyl) - 2- (hydroxymethyl) tetrahydrofuran -3- alcohol：

Antiviral activity

Another aspect of the present invention is related to the method for suppressing virus infection, and which includes treating doubtful need with the present composition The step of wanting sample or the experimenter of this suppression.

In the context of the present invention, it is doubtful to include natural or artificial material, such as Living Organism containing virulent sample； Tissue or cell culture；Biological sample, such as biological material specimens (blood, serum, urine, cerebrospinal fluid, tear, expectorant, saliva Liquid, tissue sample etc.)；Laboratory sample；Food, water or air sample；Biological material specimens, such as cell extract, especially It is the reconstitution cell of glycoprotein needed for synthesis；Deng.Generally, by the doubtful organism containing induced viral infection, which is usual for sample It is pathogenic microbes, such as oncoviruss.Sample is can be included in any medium, including water and organic solvent aqueous mixtures. Sample includes Living Organism, such as people and artificial material, such as cell culture.

If desired, the antiviral activity for applying the compounds of this invention after said composition (can be included by any means Detect the directly or indirectly method of the activity) it is observed.Determine that quantitative, the quantitative and semi-quantitative method of this activity are examined Including considering.One of commonly used above-mentioned screening technique, but, any other method for example observes the physiological property of live organism And be suitable for.

The antiviral activity of the compounds of this invention can be measured using known standard screening scheme.For example, compound Antiviral activity can be measured using following general approach.

Respiratory syncytial virus (RSV) antiviral activity and cell toxicity test

Anti- RSV is active

The antiviral activity of antagonism RSV infectious cytopathy cell protection test used in HEp-2 cells is determined. In this test, the infection of suppression virus and/or the compound for replicating produce cytoprotection for the cell killing of virus induction, Its available cytoactive reagent is carried out quantitatively.Technology used herein is document (Chapman et al., the Antimicrob for publishing Agents Chemother.2007,51 (9):The new improvement of the method described in 3346-53.).

Obtain HEp-2 cells and be maintained at from ATCC (Manassas, VI) and be supplemented with 10% hyclone and penicillin/chain In the MEM culture medium of mycin.Cell is passed on weekly twice and is maintained at sub- fusing stage (subconfluent stage).Changing Commercially available RSV strains A2 (Advanced Biotechnologies, Columbia, MD) storing solution is titrated before compound test To determine the acceptable diluent degree of the virus stock that required cytopathic effect is generated in HEp-2 cells.

In order to carry out antivirus test, HEp-2 cells are grown into be close in big Tissue Culture Flask and is merged but not complete It is complete to merge.By compound to be tested in the diluted chemical compound plate of 384- holes, with 8 or the Normalized dose response shape of 40 samples/plate Formula pre-dilution is in DMSO.3 times of serial dilution increment samples of each test compound are prepared in plate and is filled via acoustics transfer Put (Echo, Labcyte) test specimen is transferred in cell culture test 384- orifice plates with 100nl/ holes.Each diluted chemical compound Liquid is with single part or quadruplicate sample is transferred in dry bread board, and which is stored for until test will start.It is positive and cloudy Property control the two ends of plate are arranged in vertical block (1 row).

Subsequently, virus storage of the cell density of the acceptable diluent degree for being determined using previously passed titration for 50,000/ml Standby liquid prepares infectious mixture and is added to examination with compound with 20uL/ holes via automation equipment (uFlow, Biotek) Test plate.Each plate includes negative and positive control (each 16 Duplicate Samples) to produce 0% and 100% HIV suppression standard respectively. After with rsv infection, bread board is cultivated 4 days in 37 DEG C of cell culture cultivating containers.After culture, in bread board cell is added to live Power reagent C ell TiterGlo (Promega, Madison, WI), then its of short duration culture is measured in all bread boards (Envision, Perkin Elmer) fluorescence reading.The cytopathic effect of RSV inductions is determined from remaining cell activity level (suppression percentage).Suppress control relative to 0% and 100%, these numerical value are calculated for each tested concentration, and pass through non-thread Property return EC is determined with the concentration for suppressing 50% RSV induced cytopathic effects₅₀Value.Using various effectively anti-RSV instruments Positive control of the compound as antiviral activity.

Cell toxicity test in HEp-2 cells

Using cell viability reagent with previously for described in other cell types similar manner (Cihlar et al., Antimicrob Agents Chemother.2008,52(2):655-65.) with antiviral activity abreast in uninfection The cytotoxicity of test-compound is determined in HEp-2 cells.For the measurement of Compound Cytotoxicity, adopt and antiviral activity Measurement identical scheme, except for the difference that the cell receive rsv infection.On the contrary, to also with 100nl/ samples comprising pre- dilute The plate of compound is released with the cell mixture of the uninfection of 20ul/ holes addition equal densities.Then by bread board culture 4 days, Subsequently carry out cell viability using identical CellTiter Glo reagent dosages to test and measure fluorescence reading.It is unprocessed Cell and the cells that process of Jing 2uM puromycins (Sigma, St.Louis, MO) each act as 100% and 0% cell viability Control.Relative to 0% and 100% control, cell viability percentage is calculated for each test compound concentration and pass through non-thread Property return with compound reduce by 50% cell viability concentration determine CC₅₀Value.

Cell toxicity test in MT-4 cells

Obtain from NIH AIDS Research and Reference Reagent Program (Germantown, MD) MT-4 cell lines are simultaneously being supplemented with 10%FBS, 100 units/mL penicillins, 100 units/mL streptomycins and 2mM L-glutaminate RPMI-1640 culture medium (Irvine Scientific, Santa Ana, CA, catalog number (Cat.No.) 9160) in culture.It is thin using MT-4 Born of the same parents pass on weekly twice to keep cell density to be less than 0.6x 10⁶Individual cell/mL.By containing 100x concentration 3 times of serial dilutions The complete RPMI-1640 culture medium of compound (26nM to 530 μM) is inoculated into black 384- orifice plates in quadruplicate.Compound is added Afterwards, 2x 10 is added in each hole using MicroFlo liquid distributors (BioTek, Winooski, VT)³MT-4 cells simultaneously will be thin Born of the same parents are in 37 DEG C of 5%CO₂Cultivate 5 days in incubator.After culture, by cell balance to 25 DEG C and by adding 25 μ L Cell- Titer Glo vigor reagents are determining cell viability.The mixture is cultivated 10 minutes at 25 DEG C, and is read in Victor fluorescent screens It is quantitative to fluorescence signal on number device.CC₅₀Value is defined as determined by Cell-Titer Glo signals reducing cell viability 50% compound concentration.Using Pipeline Pilot Plate Data Analytics Collection softwares (Version 7.0, Accelrys, San Diego, CA) analytical data.CC₅₀Value is joined using 4- by nonlinear regression analyses Number S type dosage-response formula is calculated：Y=bottoms+(top-bottom)/(1+10^ [(LogCC50-X) * slopes]), wherein top and bottom are distinguished It is fixed at 100% and 0% cell viability.CC₅₀Value is calculated as 3 meansigma methodss ± standard deviations individually tested.

Embodiment	EC₅₀/μM	HEp-2CC₅₀/μM	MT-4CC₅₀/μM
				1	0.208	>100	59
2	6.5	>100	>114
				3	5.0	>50	>57
4	>98	>93	93
				PD1	0.556	>50	10.4

RSV RNP preparations

RSV ribonucleoproteins (RNP) complex is prepared by the improved methods of Mason et al. (1).By HEp-2 cells with 7.1x 10⁴Individual cell/cm²Density be inoculated into MEM+10% hyclones (FBS) in and by which in 37 DEG C of (5%CO₂) adherent Overnight.After adherent, the cell is infected in 35mL MEM+2%FBS with RSV A2 (MOI=5).20 hours after infection, should Culture medium is substituted with the MEM+2%FBS for being supplemented with 2 μ g/mL actinomycin D and returns to 37 DEG C up to 1 hour.Then by the cell Washed with PBS 1 time and processed 1 minute with 35mL PBS+250 μ g/mL LYSOLECITHIN SUNLECITHIN A, suction out thereafter all liq.It is described thin Born of the same parents are by they are scraped 1.2mL buffer As [50mM TRIS acetates (pH 8.0), 100mM potassium acetates, 1mM DTT and 2 μ g/mL actinomycin D] in be collected by passing repeatedly through No. 18 pins (10 times) to crack.The cell lysate is placed in ice 10 minutes, then it is centrifuged 10 minutes with 2400g at 4 DEG C.Remove supernatant (S1) and be supplemented with 1%Triton X-100's 600uL buffer Bs [10mM TRIS acetates (pH 8.0), 10mM potassium acetates and 1.5mM MgCl₂] in pass repeatedly through 18 good pins (10 times) are destroying the cell mass (P1).The cell mass of settling flux is placed in 10 minutes in ice, then at 4 DEG C with 2400g Centrifugation 10 minutes.Remove supernatant (S2) and buffer in the 600uL for being supplemented with 0.5% dexycholate and 0.1%Tween 40 Cell mass (P2) is destroyed in liquid B.The cell mass of settling flux is placed in 10 minutes in ice, then 10 is centrifuged with 2400g at 4 DEG C Minute.Collect supernatant (S3) fraction containing enrichment RSV RNP complex and albumen is determined by UV absorbances under 280nm Concentration.The RSV RNP S3 fraction of decile is stored at -80 DEG C.

RSV RNP are tested

In reaction buffer [50mM TRIS- acetass (pH 8.0), 120mM potassium acetates, 5% glycerol, the 4.5mM of 30 μ L MgCl₂, 3mM DTT, 2mM ethylene glycol-bis- (2- amino-ethyl ethers)-tetraacethyl (EGTA), 50 μ g/mL BSA, 2.5U RNasin (Promega), ATP, GTP, UTP, CTP and 1.5uCi [α-³²P] NTP (3000Ci/mmol)] in, responsive transcription thing includes 25 μ g Thick RSV RNP complex.Radiolabeled oligonucleotide used in transcriptional assays is selected Nucleotide analog matching.By cold competitive NTP with its half K_mUltimate density (ATP=20 μM, GTP=12.5 μM, UTP=6 μM and CTP=2 μM) add.Remaining three kinds of nucleotide is added with 100 μM of ultimate density.

In order to determine whether nucleotide analog suppresses RSV RNP to transcribe, added using the 6 step serial dilutions with 5 times of increments Enter compound.After 30 DEG C of cultures 90 minutes, stop the RNP with the Qiagen RLT lysis buffers of 350 μ L and react and use 96 kits RNA of Qiagen RNeasy.By the RNA of purification load RNA sample buffer (Sigma) at 65 DEG C Degeneration 10 minutes is simultaneously tested on 1.2% agarose containing 2M formaldehyde/MOPS gels.The agarose is dried and is exposed to Storm Phosphorescence imagings screen is simultaneously developed using Storm Phosphorescence imaging agent (GE Healthcare).By the non-thread of two Duplicate Samples Property regression analyses calculate by gross activity labelling transcript reduce 50% compound concentration (IC₅₀)。

List of references

1) Mason, S., Lawetz, C., Gaudette, Y., Do, F., Scouten, E., Lagace, L., Simoneau, And Liuzzi, M. (2004) Polyadenylation-dependent screening assay for respiratory B. syncytial virus RNA transcriptase activity and identification of an inhibitor.Nucleic Acids Research, 32,4758-4767.

Embodiment	IC₅₀/μM
		TP1	0.076
TP2	0.042
		TP3	0.036
TP4	0.2

Claims

1. formula (I) compound, or its pharmaceutically acceptable salt：

Wherein：

X is selected from：O, S, NH or N (C₁-C₆Alkyl)；

R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：F、Cl、OR^a、NHR^a, CN and N₃；

R³It is selected from：CN、OR^a、C₁-C₆Alkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl ,-CH₂-O-C₁-C₆Alkyl ,-CH₂-S-C₁-C₆Alkyl, C₃-C₄Cycloalkyl, azido, halogen, C₁-C₃Haloalkyl, SR^a、-CH₂-C₃-C₄Cycloalkyl ,-O-C₃-C₄Cycloalkyl and-O-C₁- C₃Haloalkyl；

Or

Work as R²For OR^aWhen, formed together with the furan nucleuss that can be connected with them of two ORa groups of 2 ' and 3 ' positions selected from Under structure：

R⁴It is selected from：H ,-C (=O) R⁶,-C (=O) OR⁶With-C (=O) NR⁶R⁷；

Or

a)R⁴For following formula group：

Wherein：

Each Y be O, S, NR,⁺N(O)(R)、N(OR)、⁺N (O) is (OR) or N-NR₂；With

W¹And W²Formation-Y together³(C(R^y)₂)₃Y³-；

Or

W¹And W²It is each independently the group of Formulas I a：

Wherein：

Each Y²It independently is key, O, CR₂、-O-CR₂-、NR、⁺N(O)(R)、N(OR)、⁺N(O)(OR)、N-NR₂, S, S-S, S (O) or S(O)₂；

Each Y³It independently is O, S or NR；

M1 is 0,1,2 or 3；

Each R^xIt independently is R^yOr be following formula：

Wherein：

Each M2a, M2b and M2c independently are 0 or 1；

M2d is 0,1,2,3,4,5,6,7,8,9,10,11 or 12；

Each R^yIt independently is H, F, Cl, Br, I, OH, R ,-C (=Y¹) R ,-C (=Y¹) OR ,-C (=Y¹)N(R)₂、-N(R)₂、-⁺N (R)₃、-SR、-S(O)R、-S(O)₂R、-S(O)(OR)、-S(O)₂(OR) ,-OC (=Y¹) R ,-OC (=Y¹) OR ,-OC (=Y¹)(N (R)₂) ,-SC (=Y¹) R ,-SC (=Y¹) OR ,-SC (=Y¹)(N(R)₂) ,-N (R) C (=Y¹) R ,-N (R) C (=Y¹)OR、-N (R) C (=Y¹)N(R)₂、-SO₂NR₂、-CN、-N₃、-NO₂,-OR or W³；

Or two R in identical carbon atoms^yThe heterocycle with 3,4,5,6 or 7 annular atoms is formed together with the carbon atom, its In annular atom be selected from O or N and every other annular atom is carbon；

Each R independently is H, (C₁-C₈) alkyl, (C₁-C₈) replace alkyl, (C₂-C₈) thiazolinyl, (C₂-C₈) replace thiazolinyl, (C₂-C₈) alkynyl, (C₂-C₈) replace alkynyl, C₆-C₁₀Aryl, C₆-C₁₀Substituted aryl, 3- to 10- circle heterocycles, the 3- for replacing To 10- circle heterocycles, 5- to 12- unit's heteroaryls, 5- to the 12- unit's heteroaryls for replacing, aryl alkyl, the aryl alkyl, miscellaneous for replacing Aryl alkyl or substituted heteroaryl alkyl；With

W³For W⁴Or W⁵；

W⁴For R ,-C (Y¹)R^y、-C(Y¹)W⁵、-SO₂R^yOr-SO₂W⁵；

W⁵Selected from phenyl, naphthyl, C₃-C₈Carbocyclic ring or 3- to 10- circle heterocycles, wherein W⁵Independently by 0,1,2,3,4,5 or 6 R^yBase Group replaces；

Each R⁶And R⁷It independently is H, (C₁-C₈) alkyl, (C₂-C₈) thiazolinyl, (C₂-C₈) alkynyl, (C₄-C₈) carbocylic radical alkyl, C₆-C₁₀ Aryl, C₆-C₁₀Substituted aryl, 5- to 10- unit's heteroaryls, 5- to the 10- unit's heteroaryls for replacing ,-C (=O) (C₁-C₈) alkane Base ,-S (O)_n(C₁-C₈) alkyl or aryl (C₁-C₈) alkyl；

Or R⁶And R⁷3- to 7- circle heterocycles are formed together with the nitrogen being connected with them, wherein any ring carbon atom of the heterocycle is appointed Choosing is by-O- ,-S- or-NR^a- substitute；

And wherein each R⁶Or R⁷Each (C₁-C₈) alkyl, (C₂-C₈) thiazolinyl, (C₂-C₈) alkynyl or aryl (C₁-C₈) alkyl is independently Halogen, hydroxyl, CN, N are selected from by one, two, three or four₃、N(R^a)₂Or OR^aSubstituent group it is optionally substituted；And it is wherein each (the C₁-C₈) alkyl one, two or three non-end carbon atom optionally by-O- ,-S- or-NR^a- substitute；Or

b)R⁴Selected from following group：

Wherein：

R⁸Selected from phenyl, 1- naphthyls, 2- naphthyls,

R⁹Selected from H and CH₃；

R¹⁰Selected from H or C₁-C₆Alkyl；With

2. the compound of claim 1, or its pharmaceutically acceptable salt, wherein X are S.

3. the compound of any one of claim 1 and 2, or its pharmaceutically acceptable salt, wherein R³It is selected from：CN、OR^a、C₁-C₄ Alkyl, C₂-C₄Thiazolinyl, C₂-C₄Alkynyl ,-CH₂-O-C₁-C₄Alkyl ,-CH₂-S-C₁-C₄Alkyl, C₃-C₄Cycloalkyl, azido, halogen Element, C₁-C₃Chlorine alkyl, C₁-C₃Bromine alkyl and C₁-C₃Fluoroalkyl.

4. the compound of any one of claim 1,2 and 3, or its pharmaceutically acceptable salt, wherein R¹It is selected from：H、CH₃、F、 Cl and NH₂；R²It is selected from：OH、F、Cl、N₃、NH₂And CN；And R³It is selected from：CN、N₃, methyl, ethyl, propyl group, vinyl, acrylic, Acetenyl, CH₂F、CHF₂、CH₂Cl、CH₂SMe and CH₂OMe。

5. the compound of any one of claim 1,2,3 and 4, or its pharmaceutically acceptable salt, which is formula (II)：

Wherein R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：F、Cl、OH、NH₂, CN and N₃；

R^a、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、Y、Y¹、Y²、Y³、W¹、W²、W³、W⁴、W⁵、M1、M2a、M2b、M2c、M2d、R^xAnd R^y As defined in claim 1.

6. the compound of any one of claim 1,2,3 and 4, or its pharmaceutically acceptable salt, which is formula (III)：

Wherein：

R²For F, Cl, OH, NH₂, CN and N₃；

R⁴For H or following formula group：

Wherein W¹And W²It is each independently OH or Formulas I a group：

Wherein：

Each Y independently is key or O；

M is 0,1,2 or 3；

Each R^xFor H, halogen or OH；

Or

R⁴Selected from H and：

Wherein：

N ' is selected from 1,2,3 and 4；

R⁷Selected from C₁-C₈Alkyl ,-O-C₁-C₈Alkyl, benzyl ,-O- benzyls ,-CH₂-C₃-C₆Cycloalkyl ,-O-CH₂-C₃-C₆Cycloalkyl And CF₃；

R⁸Selected from phenyl, 1- naphthyls, 2- naphthyls,

R⁹Selected from H and CH₃；

R¹⁰Selected from H or C₁-C₆Alkyl；

7. the compound of any one of claim 1,2,3 and 4, or its pharmaceutically acceptable salt, which is formula (VI)：

Wherein：

X is selected from：O, S and NH；

R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：F、Cl、OH、NH₂, CN and N₃；With

R³It is selected from：CN、N₃, methyl, ethyl, propyl group, vinyl, acrylic, acetenyl, CH₂F、CHF₂、CH₂Cl、CH₂SMe and CH₂OMe。

8. the compound of any one of claim 1,2,3,4,5,6 and 7, or its pharmaceutically acceptable salt, wherein X are S.

9. the compound of any one of claim 1,2,3 and 4, or its pharmaceutically acceptable salt, which is formula (IX)：

Wherein：

R¹It is selected from：H、CH₃, F, Cl and NH₂；

R²It is selected from：F、Cl、OH、NH₂, CN and N₃；With

10. the compound of any one of claim 1,2,3,4,5,6,7 and 8, or its pharmaceutically acceptable salt, wherein R¹For H。

The compound of any one of 11. claim 1,2,3,4,5,6,7 and 8, or its pharmaceutically acceptable salt, wherein R¹For F。

The compound of any one of 12. claim 1,2,3,4,5,6,7,8,9,10 and 11, or its pharmaceutically acceptable salt, Wherein R²For F.

The compound of any one of 13. claim 1,2,3,4,5,6,7,8,9,10 and 11, or its pharmaceutically acceptable salt, Wherein R²For Cl.

The compound of any one of 14. claim 1,2,3,4,5,6,7,8,9,10 and 11, or its pharmaceutically acceptable salt, Wherein R²For N₃。

The compound of any one of 15. claim 1,2,3,4,5,6,7,8,9,10,11,12,13 and 14, or which pharmaceutically may be used The salt of acceptance, wherein R³It is selected from：CN and N₃。

The compound of any one of 16. claim 1,2,3,4,5,6,7,8,9,10,11,12,13 and 14, or which pharmaceutically may be used The salt of acceptance, wherein R³It is selected from：Methyl, ethyl and propyl group.

The compound of any one of 17. claim 1,2,3,4,5,6,7,8,9,10,11,12,13 and 14, or which pharmaceutically may be used The salt of acceptance, wherein R³It is selected from：CH₂F、CHF₂And CH₂Cl。

The compound of any one of 18. claim 1,2,3,4,5 and 6, or its pharmaceutically acceptable salt, wherein R⁴Selected from base Group：

The compound of any one of 19. claim 1,2,3,4,5 and 6, or its pharmaceutically acceptable salt, wherein R⁴For：

Wherein R⁸、R⁹、R¹⁰And R¹¹As defined in claim 1.

The compound of any one of 20. claim 1,2,3,4,5 and 6, or its pharmaceutically acceptable salt, wherein R⁴For：

Wherein R⁸、R⁹、R¹⁰And R¹¹As defined in claim 1.

The compound of any one of 21. claim 1,2,3,4,5 and 6, or its pharmaceutically acceptable salt, wherein R⁴For：

Wherein n ' is selected from 1,2,3 and 4；And R⁷It is selected from：C₁-C₈Alkyl ,-O-C₁-C₈Alkyl, benzyl ,-O- benzyls ,-CH₂-C₃-C₆Ring Alkyl ,-O-CH₂-C₃-C₆Cycloalkyl and CF₃。

Any one of 22. claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20 and 21 Compound, or its pharmaceutically acceptable salt, the compound are selected from：

The method of pneumonitis viruss subfamily virus infection of 23. treatments in people, the method include to the people's administration for having this needs controlling Treat in the claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 and 22 of effective dose The compound of any one, or its pharmaceutically acceptable salt.

The method of 24. claim 23, wherein pneumonitis viruss subfamily virus infection is respiratory syncytial virus infection.

25. pharmaceutical compositions, its include claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18, 19th, any one of 20,21 and 22 compound, or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or figuration Agent.

26. are intended to the medicine for treating the infection of pneumonitis viruss subfamily virus or respiratory syncytial virus infection in people for preparing Method, the method is characterized in that usage right require 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17, 18th, any one of 19,20,21 and 22 compound, or its pharmaceutically acceptable salt.

Appoint in 27. claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 and 22 The compound of one, or its pharmaceutically acceptable salt, which is used for the pneumonitis viruss subfamily virus infection treated in people or exhales Inhale road syncytial virus infection.

Appoint in 28. claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 and 22 The compound of one or its pharmaceutically acceptable salt are being prepared for treating the viral infection of the pneumonitis viruss subfamily in people or exhaling Inhale the purposes in the medicine of road syncytial virus infection.